5-membered heteroaryl carboxamide compounds for treatment of hbv

Abstract

The present disclosure provides, in part, 5-membered heteroaryl carboxamide compounds useful for disrupting HBV core protein assembly and pharmaceutical compositions thereof and methods of treating hepatitis B (HBV) infection.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511217514.7 (22) Application Date 2021.04.21 (30) Priority Data 63 / 014,001 2020.04.22 US (62) Divisional Application Data 202180042939.2 2021.04.21 (71) Applicant Assembly Biosciences Inc. Address California, USA (72) Inventors T. Heckrodt M. Valk M. Chung (74) Patent Agency Beijing Liu Shen Law Firm 11105 Patent Attorney Liu Lei (51) Int.Cl. C07D 233 / 90 (2006.01) C07D 401 / 08 (2006.01) C07D 277 / 56(2006.01) C07D 403 / 08(2006.01) C07D 263 / 34(2006.01) C07D 471 / 04(2006.01) C07D 405 / 04(2006.01) C07D 498 / 04(2006.01) C07D 487 / 04(2006.01) A61K 31 / 4178(2006.01) A61K 31 / 4164(2006.01) A61K 31 / 4439(2006.01) A61K 31 / 4188(2006.01) A61K 31 / 421(2006.01) A61K 31 / 426(2006.01) A61K 31 / 437(2006.01) A61K 31 / 454(2006.01) A61K 31 / 5377(2006.01) A61K 31 / 5383(2006.01) A61K 31 / 4985(2006.01) A61P 31 / 20(2006.01) (54) Invention Title: Five-membered heteroarylformamide compounds for treating HBV (57) Abstract: This disclosure partially provides five-membered heteroarylformamide compounds that can be used to disrupt the assembly of HBV core proteins, pharmaceutical compositions thereof, and methods for treating hepatitis B (HBV) infection. Claims 2 pages, Description 163 pages, Serial List (electronic publication), Drawings 1 page. CN 121248511 A 2026.01.02 CN 1 21 24 85 11 A 1. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: L is a C1-4 alkylene or a halo-C1-4 alkylene; L1 and L2 are independently bonded, C1-6 alkylene, O, NRc, C(O), C(O)O, C(O)NRc, S(O)t or S(O)tNRc;X1 is NRx1; X3 is CR4R8; X4 and X6 are independently O or S; X5 is O, S or NR0; Ra, Rb and Rc are independently selected from the group consisting of hydrogen, C1-6 alkyl, halo-C1-6 alkyl and C3-6 monocyclic alkyl each time they appear; Rd is hydrogen, OH, C1-6 alkyl or C1-6 alkoxy; Rx1 is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, halo-C1-4 alkyl or C3-6 monocyclic alkyl; or Rx1 and R2 together form -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -CH2CH2CH2O-, -CH2CH2OCH2-, -CH2CH2-NH-, -CH2NHCH2-, -CH2CH2CH2NH- or -CH2CH2NHCH2- groups; R0a is independently selected from the group consisting of: hydrogen, halogen, OH, CN, NO2, RaRbN-, C1-4 alkyl, and halo-C1-4 alkyl each time it appears; R4a and R6a are independently hydrogen or C1-4 alkyl; R0, R6, and R11 are independently selected from the group consisting of: hydrogen, halogen, OH, CN, NO2, oxo, RdN=, hydrazyl, formyl, azide, silyl, siloxy, HOC(O)-, RaRbN-, RaRbNS(O)t-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo-C1-6 alkyl, hydroxy-C1-6 alkyl-, RaRbNC1-6 alkyl-, HOC(O)C1- 6-alkyl-, RaRbNC1-6alkylNRc-, C1-6alkylNRaC1-6alkylNRc-, C1-6alkoxy, halo-C1-6alkoxy, hydroxy-C1-6alkoxy-, RaRbNC1-6alkoxy-, C1-6alkoxyC1-6alkyl-, halo-C1-6alkoxyC1-6alkyl-, RaRbNC(O)-, C1-6alkylC(O)-, C1-6alkoxyC(O)-, C1-6 Alkyl C(O)O-, C1-6 alkyl S(O)q-, C1-6 alkyl S(O)tNR c-, C1-6 alkyl S(O)tC1-6 alkyl-, C1-6 alkyl S(O)tNR aC1-6 alkyl-, C3-6 cycloalkyl S(O)tC1-6 alkyl-, C1-6 alkyl C(O)C1-6 alkyl- and C1-6 alkyl C(O)OC1-6 alkyl-; R1 is a phenyl or a 5- to 6-membered monocyclic heteroaryl group, wherein the phenyl or 5- to 6-membered monocyclic heteroaryl group is optionally substituted by one, two or three independently selected R11 groups; R2 and R8 are independently selected from the group consisting of hydrogen, halogen, CN, OH, RaRbN, C1-4 alkyl, halo-C1-4 alkyl, C3-5 monocyclic alkyl, C1-4 alkoxy and halo-C1-4 alkoxy; R3 is R4 is R5-L1-, R6 or R9; ClaimsPage 1 / 2 2 CN 121248511 A R5 is R9 is R14S(O)q-L-, R14S(O)qNH-L-, or R14C(O)NH-L-; R14 is RaRbN-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, or R5-L1-; q, r, t, and w are independently selected from 0, 1, and 2 each time they appear; and v is independently selected from 0, 1, 2, and 3 each time it appears. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Rx1 is hydrogen or methyl. 3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein r is 0. 4. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen. 5. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: R1 is R11 independently selected from the group consisting of halogens, CN, C1-6 alkyl, and halo-C1-6 alkyl each time it appears; and z1 is 0, 1, 2, or 3. 6. The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R3 is 7. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R4 is R6, R5-L1-, or R9. 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein L1 is a bond. 9. A pharmaceutical composition comprising the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 10. Use of the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for treating hepatitis B (HBV) infection. Claims 2 / 2 Page 3 CN 121248511 A 5-membered heteroarylformamide compound for treating HBV

[0001] This application is a divisional application of Chinese Patent Application No. 202180042939.2, filed on April 21, 2021, entitled "5-membered heteroarylformamide compound for treating HBV", the entire contents of which are incorporated herein by reference. Background Art

[0002] Hepatitis B (HBV) causes viral hepatitis, which can further lead to chronic liver disease and increase the risk of chronic cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, approximately 2 billion people are infected with HBV, and approximately 360 million are chronically infected. HBV infection causes more than 500,000 deaths annually. HBV can be transmitted through bodily fluids: mother-to-child transmission, sexual transmission, and transmission through blood products. Children born to HBV-positive mothers may also be infected unless vaccinated at birth.

[0003] Hepatitis virus particles are formed by a lipid envelope surrounding the viral core, which is adorned with surface proteins (HBsAg). The core comprises a protein coat or capsid consisting of 120 core protein (Cp) dimers, which also contains a relaxed circular DNA (rcDNA) viral genome, as well as viral and host proteins. In infected cells, the genome is found to be a covalently closed circular DNA (cccDNA) in the host cell nucleus. cccDNA is the template for viral RNA, and therefore the template for viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (so-called pregenomic RNA or pgRNA) and viral polymerase (P). After assembly, P reverse transcribes pgRNA into rcDNA within the capsid to produce a DNA-filled viral core.

[0004] Currently, chronic HBV is primarily treated with nucleoside (acid) analogs (e.g., entecavir), which suppress the virus while the patient is on treatment, but do not eliminate the infection even after many years of treatment. Once patients begin taking nucleoside (acid) analogs, most must continue taking them or risk a life-threatening immune response due to viral rebound. Furthermore, nucleotide therapy can lead to antiviral resistance.

[0005] The only FDA-approved alternative to nucleoside (acid) analogs is treatment with interferon-alpha or pegylated interferon-alpha. Unfortunately, the incidence and profile of adverse events associated with interferon-alpha can lead to poor tolerability, and many patients cannot complete the therapy. Moreover, only a small percentage of patients are considered suitable for interferon therapy because only a small percentage are likely to have a sustained clinical response to a course of interferon therapy. Therefore, interferon-based therapies are used only for a small fraction of all confirmed patients who are selected for treatment.

[0006] Consequently, current HBV treatment ranges from palliative care to observational therapy. Nucleoside analogs suppress viral production and treat symptoms but do not affect infection. Interferon-alpha has serious side effects, is poorly tolerated by patients, and has only been successful as a limited treatment strategy in a small percentage of patients. Significant persistence requires more effective treatment for HBV infection.

[0007] This disclosure provides a 5-membered heteroarylformamide compound and pharmaceutical compositions thereof that can be used to disrupt the assembly of HBV core proteins, as well as a method for treating HBV infection.

[0008] In one aspect, this disclosure provides a compound of formula I: (Specification 1 / 163 page 4 CN 121248511 A)

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein the variables are described in the specific embodiments.

[0011] In another aspect, this disclosure provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0012] In another aspect, this disclosure provides a method for treating HBV infection in a subject in need, comprising: administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, this disclosure provides a method for treating HBV infection in a subject in need, comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0014] In addition to the above, this disclosure also relates to the following aspects:

[0015] 1. A compound of formula I,

[0016]

[0017] or a pharmaceutically acceptable salt thereof, wherein:

[0018] L is a C1-4 alkylene or a halo-C1-4 alkylene;

[0019] L1 and L2 are independently bonded, C1-6 alkylene, O, NRc, C(O), C(O)O, C(O)NRc, S(O)t or S(O)tNRc;

[0020] X1 is NRx1;

[0021] X3 is CR4R8;

[0022] X4 and X6 are independently O or S;

[0023] X5 is O, S or NRO;

[0024] Ra, Rb and Rc are independently selected from the group consisting of hydrogen, C1-6 alkyl, halo-C1-6 alkyl and C3-6 monocyclic alkyl, each time they appear.

[0025] Rd is hydrogen, OH, C1-6 alkyl, or C1-6 alkoxy;

[0026] Rx1 is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, halo-C1-4 alkyl, or C3-6 monocyclic alkyl; or Rx1 and R2 together form -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -CH2CH2CH2O-, -CH2CH2OCH2-, -CH2CH2-NH-, -CH2NHCH2-, -CH2CH2CH2NH-, or -CH2CH2NHCH2- group;

[0027] R0a is independently selected from the group consisting of hydrogen, halogen, OH, CN, NO2, RaRbN-, C1-4 alkyl, and halo-C1-4 alkyl each time it appears;

[0028] R4a and R6a are independently hydrogen or C1-4 alkyl;

[0029] R0, R6 and R11 are independently selected from the group consisting of: hydrogen, halogen, OH, CN, NO2, oxo, RdN=, hydrazyl, formyl, azide, silyl, siloxy, HOC(O)-, RaRbN-, RaRbNS(O)t-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo-C1-6 alkyl, hydroxy-C1-6 alkyl-, RaRbNC1-6 alkyl-, HOC(O)C1-6 alkyl-, RaRbNC1-6 alkylNRc-, C1-6Alkyl NRaC1-6alkyl NRc-, C1-6 alkoxy, halo-C1-6 alkoxy, hydroxy-C1-6 alkoxy-, RaRbNC1-6 alkoxy-, C1-6 (Specification 2 / 163, Page 5, CN 121248511 A) Alkyl C1-6 alkyl-, halo-C1-6 alkoxy C1-6 alkyl-, RaRbNC(O)-, C1-6 alkyl C(O)-, C1-6 alkoxy C(O)-, C1-6 alkyl C(O)O-, C1-6 alkyl S(O)q-, C1-6 alkyl S(O)tNR c-, C1-6 alkyl S(O)tC1-6 alkyl-, C1-6 alkyl S(O) tNR aC1-6 alkyl-, C3-6 cycloalkyl S(O)tC1-6 alkyl-, C1-6 alkyl C(O)C1-6 alkyl- and C1-6 alkyl C(O)OC1-6 alkyl-;

[0030] R1 is a phenyl or a 5- to 6-membered monocyclic heteroaryl, wherein the phenyl or 5- to 6-membered monocyclic heteroaryl is optionally substituted by one, two or three independently selected R11 groups;

[0031] R2 and R8 are independently selected from the group consisting of hydrogen, halogen, CN, OH, RaRbN, C1-4 alkyl, haloC1-4 alkyl, C3-5 monocyclic alkyl, C1-4 alkoxy and haloC1-4 alkoxy;

[0032] R3 is

[0033] R4 is R5-L1-, R6 or R9;

[0034] R5 is

[0035] R9 is R14S(O)q-L-, R 14S(O)qNH-L- or R14C(O)NH-L-;

[0036] R14 is RaRbN-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy or R5-L1-;

[0037] q, r, t and w are independently selected from 0, 1 and 2 each time they appear; and

[0038] v are independently selected from 0, 1, 2 and 3 each time they appear.

[0039] 2. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein Rx1 is hydrogen or methyl.

[0040] 3. The compound according to item 2 or a pharmaceutically acceptable salt thereof, wherein Rx1 is methyl.

[0041] 4. The compound according to any one of items 1 to 3 or a pharmaceutically acceptable salt thereof, wherein r is 0.

[0042] 5. A compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

[0043] 6. A compound according to any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: R1 is R11 independently selected from the group consisting of halogens, CN, C1-6 alkyl, and halo-C1-6 alkyl each time it appears; and z1 is 0, 1, 2, or 3.

[0044] 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein for each occurrence, R11 is independently selected from the group consisting of CN, F, Cl, Br, and I.

[0045] 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R1 is

[0046] 9. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R1 is

[0047] 10. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R3 is CN 121248511 A, page 3 / 163 of the specification

[0048] 11. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R4 is R6.

[0049] 12. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R4 is R5-L1-.

[0050] 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein L1 is a bond.

[0051] 14. A compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R4 is R9.

[0052] 15. A compound according to any one of items 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R8 is hydrogen, OH, or C1-6 alkoxy.

[0053] 16. A compound according to item 15, or a pharmaceutically acceptable salt thereof, wherein R8 is OH.

[0054] 17. A pharmaceutical composition comprising a compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0055] 18. A method of treating hepatitis B (HBV) infection in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof.

[0056] 19. A method of treating hepatitis B (HBV) infection in a subject in need, the method comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition of item 17. Brief Description of the Drawings

[0057] Figure 1 shows an ORTEP drawing of compound CP-AIA-227-2.

[0058] Figure 2 shows a relative stereochemical scheme of compound CP-AIA-227-2. Detailed Description

[0059] Features and other details of the present disclosure will now be described in more detail. Before further describing the present disclosure, certain terms used in the specification, examples, and appended claims are collected herein. These definitions should be referenced to other parts of the present disclosure and interpreted as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0060] I. Definitions

[0061] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight-chain or branched groups having 2 to 6 carbon atoms (referred to herein as C2-6 alkenyl). Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl, etc.

[0062] As used herein, the term "alkoxy" refers to a straight-chain or branched alkyl group connected to an oxygen (i.e., alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups having 1 to 6 carbon atoms or 1 to 4 carbon atoms, referred herein as C1-6 alkoxy and C1-4 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy, etc. Specification 4 / 163 pages 7 CN 121248511 A

[0063] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH3CH2OCH2-, CH3OCH2CH2-, and CH3OCH2-.

[0064] As used herein, the term “alkyl” refers to a saturated straight-chain or branched hydrocarbon group. Exemplary alkyl groups include, but are not limited to, straight-chain or branched hydrocarbon groups having 1 to 6 carbon atoms or 1 to 4 carbon atoms, referred to herein as C1-6 alkyl and C1-4 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. As used herein, the term "alkylene" refers to a dialkyl group.

[0065] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight-chain or branched groups having 2 to 6 carbon atoms (referred to herein as C2-6 alkynyl). Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentylyl, hexynyl, and methylpropynyl.

[0066] As used herein, the term "carbonyl" refers to a dimethyl-C(O)-.

[0067] As used herein, the term "cyano" refers to a group -CN.

[0068] As used herein, the term "cycloalkyl" refers to a saturated monocyclic hydrocarbon group having, for example, 3 to 6 carbons (referred to herein as C3-6 monocyclic alkyl) or a bicyclic hydrocarbon ring structure having, for example, 8 to 12 carbons (referred herein as C8-12 bicyclic alkyl).Cycloalkyl). For bicyclic cycloalkyl groups, the two rings can be linked by the same or different carbon atoms. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl. Exemplary bicyclic cycloalkyl groups include, but are not limited to, spiro[2.5]octyl, spiro[3.5]nonyl, bicyclo[2.2.2]octyl, bicyclo[4.1.0]heptyl, octahydrocyclopentadienyl, bicyclo[4.2.0]octyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

[0069] As used herein, the term "cycloalkenyl" refers to a partially unsaturated monocyclic hydrocarbon group having, for example, 4 to 6 carbon atoms (referred to herein as C4-6 monocyclic alkenyl) or a bicyclic hydrocarbon ring structure having, for example, 8 to 12 carbon atoms (referred herein as C8-12 bicyclic alkenyl). For bicyclic cycloalkenyl groups: 1) one or both rings may contain one or more double bonds, and 2) the two rings may be connected by the same or different carbon atoms. Exemplary monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. Exemplary bicyclic cycloalkenyl groups include, but are not limited to, spiro[2.5]oct-5-enyl, spiro[2.5]oct-4-enyl, spiro[3.5]non-5-enyl, spiro[3.5]non-6-enyl, bicyclo[4.1.0]hept-3-enyl, bicyclo[4.1.0]hept-2-enyl, and bicyclo[2.2.2]oct-2-enyl.

[0070] As used herein, the term "carbocyclic" refers to a bicyclic ring system formed by fusion of a phenyl ring with a C3-6 monocyclic alkyl or C4-6 monocyclic alkenyl ring. Examples of carbocyclic groups include, but are not limited to, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, and 1H-indenyl.

[0071] As used herein, the term “halogenated” or “halogen” refers to F, Cl, Br, or I.

[0072] As used herein, the term “halogenated alkyl” refers to an alkyl group substituted with one or more halogen atoms. For example, a halogenated C1-6 alkyl group refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms and substituted with one or more halogen atoms. Examples include, but are not limited to, CH2F-, CHCl2-, -CHF2, CF3-, CF3CH2-, CH3CF2, CF3CCl2-, and CF3CF2-.

[0073] As used herein, the term “halogenated alkoxy” refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O-CF3CH2O-, and CF3CF2O-.

[0074] As used herein, the term "heteroaryl" refers to a substance containing one to four independently chosen heteroatoms, such as nitrogen, oxygen, and sulfur. (See page 5 / 163 of the specification, CN 121248511 A)These are 5- to 6-membered monocyclic aromatic ring systems or 8- to 12-membered bicyclic aromatic ring systems. Where possible, the heteroaryl ring can be linked to adjacent groups via carbon or nitrogen. Examples of 5- to 6-membered monocyclic heteroaryl groups include, but are not limited to, furanyl, thiophenyl (also known as thienyl), pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl (also known as pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, and tetrazolyl. Examples of 8- to 12-membered bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, indolyl, isoindolyl, benzo[d]isooxazolyl, benzo[c]isooxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[c]isothiazolyl, benzo[d]thiazolyl, inzolyl, benzo[d]imidazolyl, benzo[d]imidazolyl, and benzo[d][1,2,3]triazolyl.

[0075] The term “heterocyclic alkyl” refers to a saturated 3- to 6-membered monocyclic or 8- to 12-membered bicyclic ring system containing 1 to 4 independently selected heteroatoms such as nitrogen, oxygen, and sulfur (including their oxidation states: S(O) and SO2), etc. (referred to herein as C3-6 monoheterocyclic alkyl and C8-12 diheterocyclic alkyl). Where possible, the heterocyclic alkyl ring can be linked to an adjacent group via carbon or nitrogen. Examples of C3-6 monoheterocyclic alkyl groups include, but are not limited to, azirropropyl, oxacyclopropyl, thioheteropropyl 1,1-dioxide, oxacyclobutyl, azirrobutyl, thioheterobutyl 1,1-dioxide, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, and piperazinyl. Examples of C8-12 diheterocyclic alkyl groups include, but are not limited to, 1,4-dioxaspiro[4.5]decyl and 1,5-dioxaspiro[5.5]undecyl.

[0076] The term "heterocyclic alkenyl" refers to a partially unsaturated 3- to 6-membered monocyclic or 8- to 12-membered bicyclic ring system containing one to four independently chosen heteroatoms such as nitrogen, oxygen, and sulfur (including their oxidation states: S(O) or S(O)2), referred herein as C3-6 monoheterocyclic alkenyl and C8-12 biheterocyclic alkenyl. Where possible, the heterocyclic alkenyl ring can be connected to an adjacent group via carbon or nitrogen. For bicyclic heterocyclic alkenyl groups: 1) one or both rings may contain one or more double bonds, and 2) the two rings may...Linked by the same or different ring atoms. Examples of C3-6 monoheterocyclic alkenyl groups include, but are not limited to, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-pyrazolyl, 2,3-dihydro-1H-pyrazolyl, 4,5-dihydro-1H-imidazolyl, 2,3-dihydro-1H-imidazolyl, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 4,5-dihydrothiazolyl, 2,3-dihydrothiazolyl, 4,5-dihydroisothiazolyl, 2,3-dihydroisothiazolyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 4,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 4,5-dihydroisothiazolyl, 2,3-dihydroisothiazolyl, 3,4-dihydropyridyl, 2,3- Dihydropyridyl, 2,3,4,5-tetrahydropyridyl, 1,6-dihydropyridazinyl, 4,5-dihydropyridazinyl, 3,4,5,6-tetrahydropyridazinyl, 4,5-dihydropyrimidinyl, 1,2,5,6-tetrahydropyrimidinyl, 1,2-dihydropyrimidinyl, 1,2-dihydropyrazinyl, 2,3-dihydropyrazinyl, 1,2,3,6-tetrahydropyrazinyl, 4H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 4H-1,4-thiazinyl and 3,4-dihydro-2H-1,4-thiazinyl. Examples of C8-12 dihexaneyl groups include, but are not limited to, 6,7-dihydroindolyl, 4,5-dihydroindolyl, 7,8-dihydroimidazo[1,2-a]pyridyl, 5,6-dihydroimidazo[1,2-a]pyridyl, 4,5-dihydrobenzo[d]imidazolyl, 6,7-dihydro-1H-indolyl, 4,5-dihydro-1H-indolyl, 4,5-dihydropyrazolo[1,5-a]pyridyl, and 6,7-dihydropyrazolo[1,5-a]pyridyl.

[0077] As used herein, the term "heterocyclic group" refers to a bicyclic ring system formed by (1) fusion of a phenyl ring with a 3- to 6-membered monocyclic heterocyclic alkyl or a 4- to 7-membered monocyclic heterocyclic alkenyl ring, or (2) fusion of a 5- to 6-membered monocyclic heteroaryl ring with a C3-6 cycloalkyl, C4-7 cycloalkenyl, 3- to 6-membered monocyclic heterocyclic alkyl or 4-6-membered monocyclic heterocyclic alkenyl ring. Where possible, these rings may be connected to adjacent groups via carbon or nitrogen. Examples of heterocyclic groups include, but are not limited to, isochoryl, 2H-quinolinyl, 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azacycloheptatrienyl, 5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]oxacycloheptatrienyl, 6,7-dihydro-5H,9H-[1,2,4]triazolo[3,4-c][1,4]oxacycloheptatrienyl, Specification 6 / 163 page 9 CN 121248511 A5,6,8,9-Tetrahydro-7l2-[1,2,4]triazolo[4,3-d][1,4]diazacycloheptatrienyl, 8,9-dihydro-5H-[1,2,4]triazolo[4,3-a]diazacycloheptatrienyl, 6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]diazacycloheptatrienyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridyl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridyl and 5H,9H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl.

[0078] As used herein, the term "hydroxyl (hydroxy and hydroxyl)" refers to the group -OH.

[0079] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2-, and HOCH2CH(OH)CH2-.

[0080] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxyl groups. Examples include, but are not limited to, HOCH2O-, HOCH2CH2O-, CH3CH(OH)CH2O-, and HOCH2CH(OH)CH2O-.

[0081] As used herein, the term "RaRbNC1-6alkyl-" refers to an alkyl group substituted with a RaRbN- group as defined herein. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2-, N(CH3)2CH2CH2-, and CH3CH(NH2)CH2-.

[0082] As used herein, the term “RaRbNC1-6alkoxy” refers to an alkoxy group substituted with a RaRbN- group as defined herein. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-.

[0083] As used herein, the term “oxo” means a group = O.

[0084] As used herein, when the rings of a bicyclic ring show floating connection points and / or floating substituents, for example, as shown, it indicates that the rings of the bicyclic ring can be connected via carbons on either ring and that substituents (e.g., one or more R33 groups) can be independently connected to one or both rings.

[0085] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans. The compounds or pharmaceutical compositions disclosed herein can be administered to mammals such as humans, but can also be administered to other mammals.Mammals include animals requiring veterinary treatment, such as domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, etc.). Mammals treated by the methods of this disclosure are ideally mammals wishing to treat HBV infection.

[0086] The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism, and / or partial agonism.

[0087] The term “pharmaceuticalally acceptable” includes molecular entities and compositions that do not produce adverse reactions, allergic reactions, or other harmful reactions when administered to animals or humans as required. For human administration, the formulation should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics Standards.

[0088] As used herein, the terms “pharmaceuticalally acceptable carrier” or “pharmaceuticalally acceptable excipient” refer to any and all solvents, dispersion media, coatings, isotonic and absorption-retarding agents, fillers, etc., compatible with drug administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Compositions may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0089] As used herein, the term “pharmaceutical composition” refers to a composition comprising at least one of the compounds disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0090] As used herein, the term “pharmaceuticalally acceptable salt” refers to a salt of an acidic or basic group that may be present in the compound used in the composition. Compounds that are inherently basic and included in the compositions of this disclosure are capable of forming a wide variety of salts with various organic acids and other organic compounds. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., those containing a pharmacologically acceptable anion. These non-toxic acid addition salts include, but are not limited to, malates, oxalates, hydrochlorides, hydrobroms, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucuronides, sucroseates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and dihydroxynaphthyl salts (i.e., 1,1'-methylene-di-(2-hydroxy-3-naphthylcarbamate)). The inherently acidic compounds included in the compositions of this disclosure are capable of forming basic salts with a variety of pharmacologically acceptable cations.Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds including basic or acidic moieties in the compositions of this disclosure may also form pharmaceutically acceptable salts with various amino acids. The compounds of this disclosure may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In such cases, the compound may exist as an acid addition salt, a zwitterion, or a basic salt.

[0091] As used herein, the term “therapeutic effective amount” or “effective amount” refers to the amount of the subject compound that will elicit a physiological or medical response in a tissue, system, or animal (e.g., a mammal or human) sought by an investigator, veterinarian, physician, or other clinical person. The compounds or pharmaceutical compositions of this disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventative effect.

[0092] The term “therapeutic” includes any effect that leads to disease improvement by disrupting the assembly of HBV core proteins, such as mitigation, reduction, modulation, or elimination. "Disruption" includes inhibiting HBV virus assembly and infection.

[0093] The compounds of this disclosure may contain one or more chiral centers and thus exist as stereoisomers. The term "stereoisomer" as used herein consists of all enantiomers or diastereomers. Depending on the configuration of the substituents surrounding the stereo carbon atom, these compounds may be represented by the symbols "(+)", "(-)", "R" or "S", but those skilled in the art will recognize that the structure may implicitly represent the chiral center. This disclosure covers various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be represented in nomenclature by "(±)", but those skilled in the art will recognize that the structure may implicitly represent the chiral center.

[0094] The compounds of this disclosure may contain one or more double bonds and thus exist as geometric isomers resulting from the arrangement of substituents surrounding the carbon-carbon double bond. Symbols denote bonds as single, double, or triple bonds as described herein. Substituents surrounding a carbon-carbon double bond can be represented as having a “Z” or “E” configuration, where the terms “Z” and “E” are used according to IUPAC standards. Unless otherwise stated, the structure describing the double bond encompasses both “E” and “Z” isomers. Alternatively, substituents surrounding a carbon-carbon double bond can be referred to as “cis” or “trans”, where “cis” indicates that the substituent is on the same side of the double bond, and “trans” indicates that the substituent is on opposite sides of the double bond.

[0095] The compounds of this disclosure may contain a carbocyclic or heterocyclic ring, and thus be geometric isomers resulting from the arrangement of substituents surrounding the ring. The arrangement of substituents surrounding the carbocyclic or heterocyclic ring is represented by a “Z” or “E” configuration, whichThe terms “Z” and “E” are used according to IUPAC standards. Unless otherwise stated, the structure of a ring describing a carbocyclic or heterocyclic ring encompasses both “Z” and “E” isomers. Substituents surrounding a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” indicates that the substituent is on the same side of the ring plane, and the term “trans” indicates that the substituent is on the opposite side of the ring plane. A mixture of compounds in which the substituents are located on both the same and opposite sides of the ring plane is referred to as “cis / trans”.

[0096] Individual enantiomers and diastereomers of the compounds disclosed herein may be synthesized from commercially available starting materials containing asymmetric centers or stereocenters, or by preparing racemic compounds and then synthesizing them by the resolution method well known to those skilled in the art, as described on page 8 / 163 of the specification, CN 121248511 A. Examples of these resolution methods include: (1) linking a mixture of enantiomers to a chiral auxiliaries, separating the diastereomer mixture by recrystallization or chromatography, and releasing the optically pure product from the auxiliaries; (2) forming a salt using an optically active resolving agent; (3) directly separating a mixture of optically enantiomers on a chiral liquid chromatography column; or (4) dynamically resolving using stereoselective chemical reagents or enzyme reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods such as chiral liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis is a chemical or enzymatic reaction well-known in the art in which a single reactant forms a non-equimolar mixture of stereoisomers during the formation of a new stereocenter or during the transformation of an existing stereocenter. Stereoselective synthesis encompasses the selective transformation of enantiomers and diastereomers and can utilize chiral auxiliaries. For example, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0097] The compounds disclosed herein may exist in both solvated and non-solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and this disclosure is intended to include both solvated and non-solvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound has a crystalline form.

[0098] This disclosure also includes isotopically labeled compounds of this disclosure that are identical to those described herein, except that one or more atoms are replaced with atoms having a different atomic mass or mass number than those commonly found in nature.Atoms of atomic mass or mass number. Examples of isotopes that can be added to the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl. For example, the compounds of this disclosure may have one or more H atoms replaced by deuterium.

[0099] Certain isotopically labeled compounds of this disclosure (e.g., those labeled with 3H and 14C) can be used in the determination of compound and / or substrate tissue distribution. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2H) can provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases. The isotopically labeled compounds of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents through procedures similar to those disclosed in the embodiments herein.

[0100] The term "prodrug" refers to a compound that is converted in vivo to yield the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Conversion can occur at various locations (e.g., in the intestinal lumen or during transport in the intestine, blood, or liver) through various mechanisms (e.g., via esterases, amidases, phosphatases, oxidative and / or reductive metabolism, etc.). Prodrugs are well known in the art (e.g., see Rautio, Kumpulainen et al., Nature Reviews Drug Discovery, 2008, 7, 255).

[0101] II. 5-membered heteroarylformamide compounds

[0102] In one aspect, the present disclosure provides a compound of formula I

[0103]

[0104] or a pharmaceutically acceptable salt thereof, wherein:

[0105] L is a C1-4 alkylene or a halo-C1-4 alkylene; Specification 9 / 163 pages 12 CN 121248511 A

[0106] L1 and L2 are independently bonded, C1-6 alkylene, O, NRc, C(O), C(O)O, C(O)NRc, S(O)t or S(O)tNRc;

[0107] X1 is NRx1, O or S;

[0108] X2 is O, NR13, CR13R8, C(O) or S(O)t;

[0109] X3 is O, NR4, CR4R8, C(O) or S(O)t;

[0110] X4 and X6 are independently O or S;

[0111] X5 is O, S or NRO;

[0112] Ra, Rb and Rc are independently selected from the group consisting of hydrogen, C1-6 alkyl, halo-C1-6 alkyl and C3-6 monocyclic alkyl each time they appear;

[0113] Rd is hydrogen, OH, C1-6 alkyl, or C1-6 alkoxy;

[0114] Rx1 is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, halo-C1-4 alkyl, or C3-6 monocyclic alkyl; or Rx1 and R2 together form -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -CH2CH2CH2O--CH2CH2OCH2-, -CH2CH2-NH--CH2NHCH2-, -CH2CH2CH2NH-, or -CH2CH2NHCH2- group;

[0115] R0a is independently selected from the group consisting of hydrogen, halogen, OH, CN, NO2, RaRbN-, C1-4 alkyl, and halo-C1-4 alkyl each time it appears;

[0116] R4a and R6a are independently hydrogen or C1-4 alkyl;

[0117] R0, R6 and R11 are independently selected from the group consisting of: hydrogen, halogen, OH, CN, NO2, oxo, RdN=, hydrazyl, formyl, azide, silyl, siloxy, HOC(O)-, RaRbN-, RaRbNS(O)t-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo-C1-6 alkyl, hydroxy-C1-6 alkyl-, RaRbNC1-6 alkyl-, HOC(O)C1-6 alkyl-, RaRbNC1-6 alkylNRc-, C1-6 alkylNRaC1-6 alkylNRc-, C1-6 alkoxy, halo-C1-6 alkoxy, hydroxy-C1-6 alkoxy-, RaRbNC1-6 alkoxy-, C1-6 Alkoxy C1-6 alkyl-, halogenated C1-6 alkoxy C1-6 alkyl-, RaRbNC(O)-, C1-6 alkyl C(O)-, C1-6 alkoxy C(O)-, C1-6 alkyl C(O)O-, C1-6 alkyl S(O)q-, C1-6 alkyl S(O)tNR c-, C1-6 alkyl S(O)tC1-6 alkyl-, C1-6 alkyl S(O)tNR aC1-6 alkyl-, C3-6 cycloalkyl S(O)tC1-6 alkyl-, C1-6 alkyl C(O)C1-6 alkyl- and C1-6 alkyl C(O)OC1-6 alkyl-;

[0118] R1 is a phenyl or a 5- to 6-membered monocyclic heteroaryl group, wherein the phenyl or 5- to 6-membered monocyclic heteroaryl group is optionally substituted by one, two or three independently selected R11 groups;

[0119] R2 and R8 are independently selected from the group consisting of: hydrogen, halogen, CN, OH, RaRbN, C1-4 alkyl, halo-C1-4 alkyl, C3-5 monocycloalkyl, C1-4 alkoxy, and halo-C1-4 alkoxy;

[0120] R3 is

[0121] R4 is R5-L1-, R6, or R9; or R4 and R8 together with the carbon atoms attached to them form the specification.Page 10 / 163, CN 121248511 A group;

[0122] R5 is

[0123] R9 is R14S(O)q-L-, R14S(O)qNH-L- or R14C(O)NH-L-;

[0124] R10 is

[0125] R12 is 11 / 163, CN 121248511 A

[0126] R13 is R5-L1-, R10-L1-, R6 or R9;

[0127] R14 is RaRbN-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy or R5-L1-;

[0128] q, r, t, and w are independently selected from 0, 1, and 2 each time they appear; and

[0129] v is independently selected from 0, 1, 2, and 3 each time it appears.

[0130] The following embodiments further describe compounds of formula I or pharmaceutically acceptable salts thereof. It should be understood that all chemically permissible combinations of the embodiments described herein are considered further embodiments of the invention.

[0131] In some embodiments, X1 is S.

[0132] In some embodiments, X1 is NRx1.

[0133] In some embodiments, X1 is NRx1 and Rx1 is hydrogen of methyl.

[0134] In some embodiments, X1 is NRx1 and Rx1 is methyl.

[0135] In some embodiments, X2 is CR13R8;

[0136] In some embodiments, X3 is CR4R8.

[0137] In some embodiments, L1 is a bond.

[0138] In some embodiments, L1 is a C1-6 alkylene group.

[0139] In some embodiments, r is 0.

[0140] In some embodiments, R1 is R11, which is independently selected from the group consisting of halogens, CN, C1-6 alkyl, and halo-C1-6 alkyl each time it appears; and z1 is 0, 1, 2, or 3.

[0141] In some embodiments, R11 is independently selected from the group consisting of halogens and CN each time it appears.

[0142] In some embodiments, R11 is independently selected from the group consisting of F, Cl, Br, and I each time it appears.

[0143] In some embodiments, R1 is selected from the group consisting of:

[0144] Specification 12 / 163 pages 15 CN 121248511 A

[0145] In some embodiments, R1 is

[0146] In some embodiments, R1 is

[0147] In some embodiments, X1 is NRx1, Rx1 is hydrogen or methyl, and R1 is

[0148] In some embodiments, R1 is optionally selected by one, two, or three independently from halogens, CN, C1-6 alkyl, and halogenated compounds.A 5- to 6-membered monocyclic heteroaryl group substituted with a C1-6 alkyl substituent.

[0149] In some embodiments, R1 is R11, which is independently selected from the group consisting of halogens, CN, C1-6 alkyl, and halo-C1-6 alkyl each time it appears; and z1 is 0, 1, 2, or 3.

[0150] In some embodiments, R2 is hydrogen.

[0151] In some embodiments, R2 is RaRbN;

[0152] In some embodiments, R2 is RaRbN, and Ra and Rb are independently selected from the group consisting of hydrogen and C1-6 alkyl.

[0153] In some embodiments, R2 is NH2.

[0154] In some embodiments, X1 is NRx1, Rx1 is hydrogen or methyl, R1 is and R2 is hydrogen.

[0155] In some embodiments, X1 is NRx1, Rx1 is hydrogen or methyl, R1 is and R2 is NH2.

[0156] In some embodiments, R3 is

[0157] In some embodiments, R3 is

[0158] In some embodiments, R3 is

[0159] In some embodiments, R3 is specification page 13 / 163 16 CN 121248511 A

[0160] In some embodiments, R3 is

[0161] In some embodiments, R3 is

[0162] In some embodiments, R3 is

[0163] In some embodiments, R3 is

[0164] In some embodiments, R3 is

[0165] In some embodiments, R3 is

[0166] In some embodiments, R3 is

[0167] In some embodiments, R4 is R5-L1-.

[0168] In some embodiments, R4 is R5.

[0169] In some embodiments, R4 is R6.

[0170] In some embodiments, R4 is R9. Specification 14 / 163 pages 17 CN 121248511 A

[0171] In some embodiments, R4 and R8 together form a group with the carbon atoms they are attached to.

[0172] In some embodiments, R5 is

[0173] In some embodiments, R5 is Specification 15 / 163 pages 18 CN 121248511 A

[0174] In some embodiments, R5 is

[0175] In some embodiments, R6 is C1-6 alkyl S(O)tC1-6 alkyl- or C1-6 alkyl S(O)tNR aC1-6 alkyl-.

[0176] In some embodiments, R8 is hydrogen, OH or C1-6 alkoxy.

[0177] In some embodiments, R8 is OH.

[0178] In some embodiments, R14 is RaRbN-, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkyl, or C1-6 haloalkoxy.

[0179] In some embodiments, R14 is R5-L1-.

[0180] In some embodiments, R14 is R5.

[0181] In some embodiments, X1 is NRx1; Rx1 is hydrogen or methyl; R1 is R2 is H; R3 is and R8 is hydrogen, OH, or C1-6 alkoxy.

[0182] In some embodiments, X1 is NRx1; Rx1 is hydrogen or methyl; R1 is R2 is H; R3 is (page 16 / 163 of specification, CN 121248511 A) and R8 is OH.

[0183] In some embodiments, X1 is NRx1; Rx1 is hydrogen or methyl; R1 is R2 is H; R3 is R5 and R8 are hydrogen, OH or C1-6 alkoxy.

[0184] In some embodiments, X1 is NRx1; Rx1 is hydrogen or methyl; R1 is R2 is H; R3 is R5 and R8 is OH.

[0185] In some embodiments, X1 is NRx1; Rx1 is hydrogen or methyl; R1 is R2 is NH2; R3 is R6 is C1-6 alkylS(O)tC1-6 alkyl- or C1-6 alkylS(O)tNR aC1-6 alkyl-; and R8 is hydrogen, OH or C1-6 alkoxy.

[0186] In some embodiments, X1 is NRx1; Rx1 is hydrogen or methyl; R1 is R2 is NH2; R3 is the specification page 17 / 163 20 CN 121248511 A; R6 is C1-6 alkyl S(O)tC1-6 alkyl- or C1-6 alkyl S(O)tNR aC1-6 alkyl-; and R8 is OH.

[0187] III. Pharmaceutical Compositions and Kits

[0188] In another aspect, this disclosure provides pharmaceutical compositions comprising compounds of formula I or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. In particular, this disclosure provides pharmaceutical compositions comprising compounds of this disclosure formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, oral, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the extent and severity of the condition being treated and on the characteristics of the specific compound used. For example, the disclosed compositions may be formulated as unit doses and / or may be formulated for oral or subcutaneous administration.

[0189] In another aspect, this disclosure provides a pharmaceutical composition comprising any combination of compounds according to the embodiments described herein, or pharmaceutically acceptable salts and / or stereoisomers thereof.

[0190] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation containing one or more compounds of this disclosure as active ingredients mixed with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application (e.g., in solid, semi-solid, or liquid form). The active ingredient may be compounded, for example, with a non-toxic, pharmaceutically acceptable carrier commonly used in tablets, granules, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable forms. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce a desirable effect on the course or condition of the disease.

[0191] To prepare solid compositions such as tablets, the main active ingredient may be mixed with a pharmaceutical carrier (e.g., a conventional tableting ingredient, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, calcium hydrogen phosphate, or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformed composition containing a homogeneous mixture of the compounds of this disclosure or pharmaceutically acceptable non-toxic salts thereof. When these preformed compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, and thus the composition can be readily subdivided into unit dosage forms of equal effective amounts, such as tablets, pills, and capsules.

[0192] In solid dosage forms (capsules, tablets, pills, sugar pills, powders, granules, etc.) for oral administration, the subject composition is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or calcium hydrogen phosphate and / or any of the following substances: (1) fillers or fillers such as starch, lactose, sucrose, glucose, mannitol and / or silica; (2) binders such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants such as glycerin; (4) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds; (7) humectants such as, For example, acetyl alcohol and glyceryl monostearate, etc.; (8) adsorbents such as kaolin and bentonite clay, etc.; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) colorants. In the case of capsules, tablets and pills, the composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules using such excipients such as lactose or toffee and high molecular weight polyethylene glycol, etc.

[0193] Tablets may optionally be made by compression or molding with one or more excipients. Compressed tablets may useBinders (e.g., gelatin or hydroxypropyl methylcellulose, etc.), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch or croscarmellose sodium, etc., as per instructions 18 / 163 pages 21 CN 121248511 A), surfactants, or dispersants are used to prepare the tablets. Molded tablets can be prepared by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms such as sugar pills, capsules, pellets, and granules can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field.

[0194] Compositions for inhalation or inhalation include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the main composition, the liquid dosage form may also contain inert diluents commonly used in the art (e.g., water or other solvents), solubilizers and emulsifiers (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, etc.), oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil, etc.), glycerin, tetrahydrofuranol, polyethylene glycol and dehydrated sorbitan fatty acid esters, cyclodextrin and mixtures thereof.

[0195] In addition to the main composition, the suspension may also contain suspending agents, such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitan and dehydrated sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0196] Formulations for rectal or vaginal application may be presented as suppositories, which can be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates, etc. The suppository is solid at room temperature but liquid at body temperature, and thus will melt in the body cavity and release the active ingredient.

[0197] Dosage forms for transdermal application of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0198] In addition to the subject composition, ointments, pastes, creams, and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragacanth gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0199] In addition to the main composition, the powder and spray may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamine powders or mixtures thereof. The spray may additionally contain a conventional propellant, such as...Examples include chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0200] Alternatively, the compositions and compounds of this disclosure can be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome preparations, or solid particles containing the compound. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Acoustic nebulizers can be used because they minimize the reagent's exposure to shear, which could lead to degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are prepared by co-formulating an aqueous solution or aqueous suspension of the subject composition with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers can vary depending on the specific subject composition required, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0201] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Specification 19 / 163 pages 22 CN 121248511 A

[0202] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil, etc.), and injectable organic esters (e.g., ethyl oleate and cyclodextrin, etc.). Suitable flowability may be maintained, for example, by using coating materials such as lecithin, by maintaining a suitable particle size in the case of dispersions, and by using surfactants.

[0203] In another aspect, this disclosure provides an enteric pharmaceutical formulation comprising the disclosed compound and an enteric-coated material; and a pharmaceutically acceptable carrier or excipient thereof. An enteric-coated material is a polymer that is substantially insoluble in the acidic environment of the stomach and soluble primarily in intestinal fluid at a specific pH. The small intestine is the portion of the gastrointestinal tract (intestine) located between the stomach and the large intestine, comprising the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the terminal ileum is about 7.5. Therefore, enteric-coated materials are suitable for use at pH values ​​below, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, and about...It is insoluble below pH 6.8, approximately 7.0, approximately 7.2, approximately 7.4, approximately 7.6, approximately 7.8, approximately 8.0, approximately 8.2, approximately 8.4, approximately 8.6, approximately 8.8, approximately 9.0, approximately 9.2, approximately 9.4, approximately 9.6, approximately 9.8, or approximately 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyethylene glycol acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose hexahydrophthalate, cellulose propionate, cellulose maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate and methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez Es series), ethyl methacrylate-methyl methacrylate-trimethylchloroethyl acrylate ammonium copolymers, natural resins (such as corn gluten, shellac, and copal collophorium), and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit). FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl30D, Coateric, and Aquateric, etc.). The solubility of each of the above materials is known or can be readily determined in vitro. The above is a list of possible materials, but those skilled in the art who benefit from this disclosure will recognize that it is not a comprehensive list, and other enteric-coated materials will be of interest to the purposes of this disclosure.

[0204] Advantageously, this disclosure also provides kits for use by consumers, for example, who require treatment for HBV infection. Such kits include suitable dosage forms, such as those described above, and instructions for use describing methods of using such dosage forms to mediate, reduce, or prevent HBV infection. The instructions for use will instruct consumers or healthcare professionals to administer the dosage form according to administration methods known to those skilled in the art. Advantageously, such kits can be packaged and sold in single or multiple kit units. An example of such kits is so-called blister packs. Blister packs are well known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). Blister packaging typically consists of a foil covered with a preferred transparent plastic material.The packaging consists of a rigid sheet of material. During the packaging process, a recess is formed in the plastic foil. The recess has the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed in the recess and the relatively rigid sheet of material is sealed to the plastic foil on the foil side opposite to the direction in which the recess is formed. Thus, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the sheet is strong enough that the tablet or capsule can be removed from the blister pack by manually applying pressure to the recess to form an opening at the recess location in the sheet. The tablet or capsule can then be removed through said opening.

[0205] Ideally, a memory aid may be provided on the kit, for example, in the form of a number next to the tablet or capsule, so that the number corresponds to the number of days of the regimen in which the tablet or capsule should be taken. Another example of such a memory aid, as described in the instruction manual 20 / 163 pages 23 CN 121248511 A, is a schedule printed on a card, for example, as shown below, “Week 1, Monday, Tuesday…etc…Week 2, Monday, Tuesday…etc.” Other variations of the memory aid will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules taken on a given day. Additionally, a daily dose of the first compound can consist of one tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0206] IV. Method

[0207] In another aspect, a method for treating hepatitis B infection in a patient in need is provided, comprising administering an effective amount of a disclosed compound to a subject or patient, and / or administering a first disclosed compound and optionally administering additional, different disclosed compounds. In another embodiment, a method for treating hepatitis B infection in a patient in need is provided, comprising administering a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising a disclosed compound or two or more disclosed compounds and a pharmaceutically acceptable excipient to a subject or patient.

[0208] For use in this respect, the appropriate dosage is contemplated to vary, for example, depending on the specific compound used, the mode of administration, and the nature and severity of the infection to be treated, as well as the specific infection to be treated, and within the authority of the treating physician. Typically, the indicated dosage can range from about 0.1 μg / kg body weight to about 1000 μg / kg body weight. In some cases, the dosage of the compound may be less than 400 μg / kg body weight. In other cases, the dosage may be less than 200 μg / kg body weight. In still other cases, the dosage can range from about 0.1 μg / kg body weight to about 100 μg / kg body weight. The dosage can be conveniently administered once daily, or in split doses at most, for example, four times daily, or in a sustained-release form.

[0209] The compounds of this disclosure can be administered by any convenient route, particularly: for example, in tablet or capsule form, via suppository for intravenous, topical, oral, or intranasal administration, or for example, in the form of injectable solutions or suspensions for intravenous, intramuscular, subcutaneous, or intraperitoneal injection for parenteral administration. Suitable formulations and pharmaceutical compositions will include those formulations and pharmaceutical compositions conventionally formulated using one or more physiologically acceptable carriers or excipients, as well as those known and commercially available formulations and pharmaceutical compositions currently used in clinical settings. Thus, the compounds can be formulated for oral, oral, topical, parenteral, rectal, or transdermal administration, or in forms suitable for administration by inhalation or blowing (oral or nasal).

[0210] For oral administration, the pharmaceutical composition may be in the form of tablets or capsules formulated by conventional methods with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium carboxyacetic acid starch); or humectants (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups, or suspensions, or they may be presented as dry products prepared prior to use with water or other suitable solvents. Such liquid preparations can be prepared by conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous solvents (e.g., almond oil, oily esters, ethanol, or fractionated vegetable oils); and preservatives (e.g., methylparaben or propylparaben or sorbic acid). The preparations may also suitably contain buffer salts, flavorings, colorings, and sweeteners as needed.

[0211] Preparations for oral administration can also be suitably formulated to deliver a controlled or sustained release of the active compound over an extended period. For oral administration, the compositions can be in the form of tablets or lozenges formulated using conventional methods known to those skilled in the art. Specification 21 / 163 pages 24 CN 121248511 A

[0212] The disclosed compounds can also be formulated for parenteral administration by injection, such as by bolus injection, or continuous infusion. Injectable formulations may be presented as unit dosage forms with added preservatives, such as in ampoules or multi-dose containers. The composition may be in the form of a suspension, solution, or emulsion, such as in an oily or aqueous solvent, and may contain additives such as suspending agents, stabilizers, and / or dispersants. Alternatively, the compound...It can be in powder form prepared prior to use with a suitable solvent such as sterile, pyrogen-free water. The compound can also be formulated as a suppository or retention enema for rectal administration, such suppositories or retention enemas containing, for example, a conventional suppository matrix such as cocoa butter or other glycerides.

[0213] Methods and compositions including a second active agent or administering a second active agent are also contemplated herein. For example, in addition to HBV infection, a subject or patient may further suffer from HBV infection-related comorbidities, i.e., diseases and other adverse health conditions associated with, aggravated by, or induced by HBV infection. The disclosed compound is contemplated herein in combination with at least one other agent previously shown to be used to treat these HBV infection-related conditions.

[0214] In some cases, the disclosed compound may be administered as part of a combination therapy in combination with one or more antiviral agents. Examples of antiviral agents include nucleoside analogs, interferon-alpha, and other assembly effectors, such as heteroaryl dihydropyrimidines (HAPs), such as methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1). For example, this document provides a method of treating a patient with hepatitis B infection, comprising administering to the patient a first amount of the disclosed compound and a second amount of an antiviral or other anti-HBV agent, such as a second amount of a second compound selected from the group consisting of: HBV capsid assembly promoters (e.g., GLS4, BAY 41-4109, AT-130, DVR-23 (e.g., as depicted below),

[0215]

[0216] NVR 3-778, NVR1221 (by code); and N890 (as depicted below):

[0217]

[0218] Other capsid inhibitors, such as those disclosed in the following patent applications incorporated herein by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847, WO2014033176, WO2014033167 and WO2014033170; nucleoside (acid) analogs that interfere with viral polymerases, such as entecavir (Baraclude), lamivudine (Epivir-HBV), telbivudine (Tyzeka, Sebivo), adefovir dipivoxil (Hepsera), tenofovir (Viread), tenofovir alafenamide fumarate (TAF), tenofovir prodrugs (e.g., AGX-1009), L-FMAU (clavidine), LB80380 (besififovir), and: Instructions for Use.22 / 163 Page 25 CN 121248511 A

[0219]

[0220] Virus entry inhibitors, such as Myrcludex B and related lipopeptide derivatives; HBsAg secretion inhibitors, such as REP 9AC' and related nucleic acid-based amphiphilic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15, as described below:

[0221]

[0222] and BM601 as described below:

[0223]

[0224] Nucleocapsid formation or integrity disruption agents, such as NZ-4 / W28F:

[0225]

[0226] cccDNA formation inhibitors, such as BSBI-25, CCC-0346, CCC-0975 (as described below):

[0227]

[0228] HBc directed transbodies, such as those located at / / dx.doi.org / Wang Y et al., Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), described in 10.1016 / j.intimp.2015.01.028; antiviral core protein mutants (e.g., Cp183-V124W and related mutations, as described in WO / 2013 / 010069 and WO2014 / 074906, which are incorporated herein by reference); HBx-interaction inhibitors, such as RNAi, antisenses, and nucleic acid-based polymers targeting HBV RNA; for example, RNAi (e.g., ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV) or nucleic acid-based polymers: (REP 2139-Ca); Immunoassay Instructions 23 / 163 pages 26 CN 121248511 A Stimulants, such as interferon α2a (Rofersin), Intron A (interferon α2b), Pegasys (pegylated interferon α2a), polyethylene glycol IFN 2b, IFNλ1a and PEG IFNλ1a, Wellferon, Rofersin, Recombinant human lymphotoxin β-receptor agonists such as CBE11 and BS1, etc.; Non-interferon immunostimulants, such as thymosin α-1 (Zadaxin) and interleukin-7.(CYT107); TLR-7 / 9 agonists such as GS-9620, CYT003, Resiquimod, etc.; cyclophilin inhibitors such as NVP018, etc.; OCB-030; SCY-635; arapovir; NIM811 and related cyclosporine analogs; vaccines such as GS-4774, TG1050, core antigen vaccines, etc.; SMAC mimics such as birinapant and other IAP-antagonists, etc.; epigenetic regulators such as KMT inhibitors (EZH1 / 2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g., OICR-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD, etc. HDM inhibitors and brominated domain antagonists; kinase inhibitors, such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors; STING agonists; ribavirin; N-acetylcysteine; NOV-205 (BAM205); nitrozonide (Alinia), tezolinide; SB 9200 small molecule nucleic acid hybrid (SMNH); DV-601; arbidol; FXR agonists (such as GW 4064 and Fexaramin); antibodies, therapeutic proteins, gene therapies, and biologics targeting viral components or interacting with host proteins.

[0229] In some embodiments, this disclosure provides a method of treating hepatitis B infection in a patient in need, comprising administering a first compound selected from any of the disclosed compounds and one or more other HBV agents, each of which is selected from HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, nucleocapsid formation disruptors, cccDNA formation inhibitors, antiviral core protein mutants, HBc-directed transbodies, HBV RNA targeting RNAi, immunostimulants, TLR-7 / 9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimics, epigenetic regulators, kinase inhibitors, and STING agonists. In some embodiments, this disclosure provides a method of treating hepatitis B infection in a patient in need, comprising administering an amount of the disclosed compound and administering another HBV capsid assembly promoter.

[0230] In some embodiments, the first and second amounts together constitute a pharmaceutically effective amount. The first amount, the second amount, or both may be equal to, higher than, or lower than the effective amount of each compound administered as a monotherapy. Therapeutic effective doses of the disclosed compounds and antiviral drugs can be administered to the subject co-administered, i.e., in a given order or by the same or different administration methods.The medication may be administered to the subject either simultaneously or alone. In some cases, it may be advantageous to begin administration of the publicly available compound first, for example, one or more days or one or more weeks before starting antiviral medication. Furthermore, additional medications may be given in combination with the above-mentioned combination therapies.

[0231] In another embodiment, the disclosed compound may be conjugated to a detection moiety (e.g., a fluorophore moiety (such moiety may re-emit a certain light frequency after, for example, binding to a virus and / or after photon excitation) (e.g., directly covalently bound to or bound via a molecular linker to the free carbon, nitrogen (e.g., amino group) or oxygen (e.g., active ester) of the disclosed compound). Contemplated fluorophores include 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as luciferin, rhodamine, anthocyanins, indole-carbocyanins, anthraquinones, fluorescent proteins, aminocoumarins, methoxycoumarins, hydroxycoumarins, Cy2, Cy3, etc. Such disclosed compounds conjugated to a detection moiety may be used, for example, in methods for detecting HBV or HBV infection pathways in vitro or in vivo; and / or in methods for evaluating the bioactivity of new compounds.

[0232] V. Examples

[0233] The compounds described herein can be prepared in many ways based on the teachings contained herein and synthetic steps known in the art. In the description of the synthetic methods described below, it should be understood that, unless otherwise stated, all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration and processing steps, can be selected as the standard conditions for the reaction as specified in the specification 24 / 163 page 27 CN 121248511 A. Those skilled in the art of organic synthesis will understand that functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be obvious to those skilled in the art, and therefore alternative methods are indicated. The starting materials used in the examples are either commercially available or readily prepared from known materials by standard methods.

[0234] At least some of the compounds identified herein as “intermediates” are also contemplated as compounds of this disclosure.

[0235] Abbreviations:

[0236] AcOH Acetic acid

[0237] ACN Acetonitrile

[0238] Boc2O Ditert-butyl dicarbonate

[0239] nBuLi n-Butyllithium

[0240] DCM Dichloromethane

[0241] DIAD Diisopropyl azodicarbonate

[0242] DIEA Diisopropylethylamine

[0243] DMF N,N-Dimethylformamide

[0244] DMSO Dimethyl sulfoxide

[0245] DPPF 1,1'-Bis(diphenylphosphine)ferrocene

[0246] EA,EtOAc Ethyl acetate

[0247] Et3N Triethylamine

[0248] HATU (Azabenzotriazole Tetramethylurea Hexafluorophosphate)

[0249] h,hr hours

[0250] HPLC (High Performance Liquid Chromatography)

[0251] LCMS (Liquid Chromatography-Mass Spectrometry)

[0252] MeOH (Methanol)

[0253] NMO (N-Methylmorpholine-N-oxide)

[0254] NBS (N-Bromosuccinimide)

[0255] PE (Petroleum Ether)

[0256] iPrOH (Isopropanol)

[0257] rt,rt (Room Temperature)

[0258] SFC (Supercritical Fluid Chromatography)

[0259] TEA (Triethylamine)

[0260] TFA (Trifluoroacetic Acid)

[0261] THF (Tetrahydrofuran)

[0262] TLC (Thin Layer Chromatography)

[0263] XPhos (2-Dicyclohexylphosphine-2',4',6'-Triisopropylbiphenyl)

[0264] Scheme I Instructions for Use 25 / 163 Page 28 CN 121248511 A

[0265]

[0266] Scheme II

[0267]

[0268] Scheme III

[0269]

[0270] Scheme IV Specification 26 / 163 Page 29 CN 121248511 A

[0271]

[0272] Scheme V

[0273]

[0274] Scheme VI Specification 27 / 163 Page 30 CN 121248511 A

[0275]

[0276] Scheme VII

[0277]

[0278] Analysis of the final compound using LCMS:

[0279] Method A: X-Bridge BEH C-18 (3x50mm x 2.5μm); Mobile phase: A; 0.025% formic acid / H2O; B: CH3CN; Injection volume: 2 μL; Flow rate: 1.2 mL / min; Column temperature: 50 °C; Gradient program: 2% B to 98% B in 2.2 min, hold for 3 min, B concentration of 2% at 3.2 min, until 4 min.

[0280] Method B: X-select CSH 18 (3x50 mm x 2.5 μm); Mobile phase: A; 0.025% formic acid / H2O; B: CH3CN; Injection volume: 2 μL; Flow rate: 1.2 mL / min; Column temperature: 50 °C; Gradient program: 0% B to 98% B in 2 min, hold for 3 min, B concentration of 0% at 3.2 min, until 4 min.

[0281] Method C: X-select CSH 18 (3x50mm x 2.5μm); Mobile phase: A; 0.05% formic acid / H2O: CH3CN (Instructions for use 28 / 163 pages, CN 121248511 A)(95:5); B: 0.05% formic acid / CH3CN; injection volume 2μL; flow rate: 1.2mL / min; column temperature: 50℃; gradient program: 0%B to 98%B in 2 minutes, hold for 3 minutes, B concentration is 0% at 3.2 minutes, until 4 minutes are reached.

[0282] Method D: X-select CSH C18 (3x50mm x 2.5μm); mobile phase: A; 2mM in ammonium bicarbonate; B: CH3CN; injection volume: 2μL; flow rate: 1.2mL / min; column temperature: 50℃; gradient program: 0%B to 98%B in 2 minutes, hold for 3 minutes, B concentration is 0% at 3.2 minutes, until 4 minutes are reached.

[0283] Method E: X-select CSH 18 (3x50mm x 2.5μm); Mobile phase: A; 0.05% formic acid / H2O; B: CH3CN; Injection volume: 2μL; Flow rate: 1.5mL / min; Column temperature: 50℃; Gradient program: 0% B to 100% B in 1.5 min, hold for 2.2 min, B concentration is 0% at 2.6 min, until 3 min is reached.

[0284] General procedure for amidation:

[0285] Method A (amide coupling using EDC.HCl): EDC.HCl (1.1 equivalent), HOBt (1.1 equivalent) and the corresponding amine (1 equivalent) are added to a stirred solution of carboxylic acid (1 equivalent) in 1,4-dioxane (5.84mL / mmol) at 0℃ and stirred for 5 min. DIPEA (3 equivalents) was added to the solution, and the resulting reaction mixture was stirred overnight at 90°C. After completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and water, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain a crude compound, which was purified by silica gel column chromatography / preparative HPLC to obtain the desired compound.

[0286] Method B (amide coupling using HATU): DIPEA (2-3 equivalents) and HATU (1.5-2.5 equivalents) were added to a stirred solution of acid compound (1.1 to 1.2 equivalents) in DMF / DCM (1.01 mL / mmol) at 0°C and stirred for 5 minutes. The corresponding amine (1 equivalent) was added to the solution. The resulting reaction mixture was stirred at room temperature for 12-16 hours. After completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC or column chromatography to obtain the desired compound.

[0287] Method C (AlMe3-mediated amidation): The corresponding aniline (1.1 equivalent) was subjected to DCM / methyl etherification at 0°C under an argon atmosphere.AlMe3 (2M in toluene, 2.5 equivalents) was added to a stirred solution of benzene (3 mL / mmol), and the reaction mixture was stirred at 0 °C for 10 min and then stirred at room temperature for 1 h. The corresponding ester compound (1 equivalent) was added to the solution at 0 °C under an argon atmosphere, and the resulting reaction mixture was refluxed at 100 °C for 16 h. After completion, the reaction mixture was cooled to 0 °C; slowly quenched with 1N HCl aqueous solution, and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude compound was purified by washing with methanol to obtain the desired compound.

[0288] Method D (amide coupling using acyl chloride / derivative): TEA (1.5–3 equivalents) was added to a stirred solution of amine compound (1 equivalent) in DCM (1.01 mL / mmol) at 0 °C and stirred for 5 min. The corresponding acyl chloride / carbamoyl chloride / chloroformate (1.1–1.5 equivalents) was slowly added to the solution at 0 °C, and the reaction mixture was stirred at room temperature until complete. After completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate / DCM. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by preparative HPLC or column chromatography to obtain the desired compound.

[0289] General procedure for the Grignard reaction:

[0290] Method A (at lower temperatures): Grignard reagent (10 equivalents) was slowly added to a stirred solution of the ketone compound (1 equivalent) in dry THF (0.2 mL / mmol) at -78°C via a glass syringe under an inert atmosphere. The reaction mixture was stirred at the same temperature for 4 hours, followed by stirring at room temperature for 2 hours. After completion, the reaction mixture was diluted with saturated ammonium chloride aqueous solution and extracted with ethyl acetate / DCM. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated on a rotary evaporator (page 29 / 163, CN 121248511 A) to obtain the crude compound. The crude compound was purified by column chromatography or preparative HPLC to obtain the desired compound.

[0291] General method for Suzuki coupling:

[0292] Method A: Add Na2CO3 (2-3 equivalents) to a mixture of the halogenated compound (1 equivalent) and the corresponding boric acid / boronic acid ester (1.2-1.5 equivalents) in 1,4-dioxane:water (4:1) (2.17 mL / mmol) and purify with argon for 15 minutes. Add PdCl2 (dppf) (0.1 equivalent) to the solution and continue purifying with argon for another 10 minutes. Stir the resulting reaction mixture at 100°C for 12-16 hours. After the reaction is complete, filter the reaction mixture through 545 and evaporate to dryness. Remove the residue...The compound was placed in ethyl acetate, washed with water, then with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography or preparative HPLC to obtain the desired compound.

[0293] General procedure for hydrogenation:

[0294] Method A: 20% Pd / C (20 wt% olefin compound) was added to a stirred solution of an olefin compound (1 equivalent) in EtOAc (2.67 mL / mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 40–50 °C for 4–7 hours under a hydrogen atmosphere (100 psi). After completion, the reaction mixture was filtered through a 545 pad and washed with EtOAc / methanol. The filtrate was concentrated under reduced pressure to obtain the compound, which was purified by silica gel column chromatography or preparative HPLC to obtain the desired compound.

[0295] General procedure for ketone reduction:

[0296] Method A: NaBH4 (1-2 equivalents) was added to a stirred solution of the ketone compound (1 equivalent) in EtOH / MeOH (5 volumes) (4.7 mL / mmol) at 0 °C under an argon atmosphere and stirred at room temperature for 2-6 hours. After completion, the reaction mixture was concentrated under vacuum, the residue was diluted with water and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum and purified by silica gel column chromatography / preparative HPLC to obtain the desired compound. Note: THF (1 volume) was also added as a co-solvent for the substrate, which has poor solubility in alcohol solvents.

[0297] Intermediate 1

[0298]

[0299] 5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yltrifluoromethanesulfonate. Tf₂O (89.8 g, 318.5 mmol) was added dropwise to a solution of 1,3,3a,4,6,6a-hexahydrocyclopentadien-2,5-dione (40.0 g, 289.5 mmol) and pyridine (24.0 g, 304.0 mmol) in DCM (600 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. Brine (300 mL) was added, and the aqueous layer was extracted with DCM (200 mL x 3). The organic layer was separated, dried over Na₂SO₄, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography using 8:1 (v / v) petroleum ether / ethyl acetate to give 5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yltrifluoromethanesulfonate, which is a yellow oil. 1H NMR (400MHz, CDCl3): δ5.63 (q ,J=1.92Hz,1H) ,3.57‑3.50(m,1H) ,3.14‑3.00(m,2H) ,2.67‑2.58(m,1H) ,2.56‑2.40 (m,2H) ,2.34‑2.26(m,1H) ,2.17(ddd,J=19.14,7.34,1.63Hz,1H)ppm.

[0300] Intermediate 2

[0301]

[0302] 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one. A mixture of 5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl trifluoromethanesulfonate (110.0 g, 407.0 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (108.5 g, 427.4 mmol), Pd(dppf)Cl2 (8.9 g, 12.2 mmol) and potassium acetate (119.7 g, CN 121248511 A 1221.0 mmol) in dioxane (1000 ml) was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was filtered through a pad, and the filter cake was washed with EtOAc (250 mL x 3). The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography using 8:1 petroleum ether / ethyl acetate to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one, which is a yellow oil. 1H NMR (400MHz, CDCl3): δ 6.37 (q, J = 2.08Hz, 1H), 3.54–3.41 (m, 1H), 3.05–2.93 (m, 1H), 2.79 (ddt, J = 16.48, 7.58, 2.64, 2.64Hz, 1H), 2.55–2.24 (m, 4H), 2.07–1.95 (m, 1H), 1.28 (s, 13H) ppm.

[0303] Intermediate 3

[0304]

[0305] Methyl 2,4-dibromo-1-methyl-1H-imidazolium-5-carboxylate. NBS (78.3 g, 414.8 mmol) and AIBN (1.95 g, 11.9 mmol) were added to a solution of methyl 1-methyl-1H-imidazolium-5-carboxylate (16.6 g, 118.5 mmol) in CHCl3 (200 mL). The reaction mixture was stirred at 60 °C for 24 hours. The mixture was concentrated and purified by column chromatography (Rf = 0.4, PE:EA = 5:1) to give methyl 2,4-dibromo-1-methyl-1H-imidazolium-5-carboxylate (22.2 g, 63% yield) as a yellow solid.

[0306] Intermediate 4

[0307]

[0308] N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide. NBS (78.3 g, 414.8 mmol) and AIBN (1.95 g, 11.9 mmol) were added to a solution of methyl 1-methyl-1H-imidazolium-5-carboxylate at room temperature.A solution of acid (10 g, 83 mmol), 3-chloro-4-fluoroaniline (18 g, 124 mmol), and Et3N (16 g, 160 mmol) in DMF (100 mL) was supplemented with HATU (63 g, 160 mmol). The reaction mixture was stirred overnight at 25 °C and then poured into water (200 mL). A yellow solid formed from the solution, which was filtered and dried to provide N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide, a pale white solid. TLC; (50% ethyl acetate / petroleum ether) (Rf: 0.3). MS calculations: C11H9ClFN3O: 253.0; Found: 254.1 [M+1]+.

[0309] Intermediate 5

[0310]

[0311] 2,4-Dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide. NBS (10 g, 60 mmol) and AIBN (0.25 g, 1.5 mmol) were added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide (4 g, 15 mmol) in CHCl3 (100 mL) at room temperature. The reaction mixture was stirred at 50 °C for 18 hours. The mixture was evaporated under vacuum to give a yellow residue. The residue was purified by silica gel column chromatography to give 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide, a yellow solid. TLC; 40% ethyl acetate / petroleum ether (Rf: 0.3). MS calculation: C11H7Br2ClFN3O: 408.9; Actual: 411.2 [M+2]+.

[0312] Alternative synthesis of 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide. HATU (13.3 g, 35.0 mmol) and DIPEA (9.69 g, 175 mmol) were added to a solution of 2,4-dibromo-1-methyl-1H-imidazolium-5-carboxylic acid (9.94 g, 35.0 mmol) in DMF (50 mL). The reaction mixture was stirred at 0 °C for 1 hour. Subsequently, 3-chloro-4-fluoroaniline (6.1 g, 42.0 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The mixture was added dropwise to water (600 mL), and the resulting precipitate was filtered to provide 2,4-dibromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide (12.5 g, 87% yield), which was a yellow solid.

[0313] Intermediate 6

[0314]

[0315] 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide. The mixture was added dropwise to 2,4-dibromo-N-(3-1.1 g (2.0 mmol) of chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide was slowly added to a solution of CH3MgI (2 mL, 4.0 mmol) in THF (50 mL). The reaction mixture was stirred at 50 °C for 4 hours, then decanted into water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to give 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide as a yellow solid. TLC; 50% ethyl acetate / petroleum ether (Rf: 0.3). MS calculation: C11H8BrClFN3O: 331.0; actual: 332.1 [M+1]+.

[0316] An alternative procedure for the synthesis of 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. The title compound was synthesized following the general amidation procedure (method C) described above to give 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide, which is a brown solid. TLC; 30% EtOAc / hexane (Rf: 0.45); 1H NMR (DMSO-d6, 400MHz): δ 10.41 (s, 1H), 7.96 (dd, J = 6.8, 2.4 Hz, 1H), 7.85 (s, 1H), 7.63–7.60 (m, 1H), 7.43 (t, J = 9.6 Hz, 1H), 3.75 (s, 3H); LCMS calculated: C11H8BrClFN3O: 331.0; Measured: 332.1 [M+1]+.

[0317] Intermediate 7

[0318]

[0319] N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. 4-Bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide (600 mg, 1.8 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one (448 mg, 1.8 mmol), Pd(dppf)Cl2 (62 mg, 0.077 mmol), and K3PO4 (814 mg, 3.6 mmol) were stirred at 100 °C for 4 hours under N2 in a mixture of dioxane (20 mL) and water (4 mL). EtOAc (20 mL) was then added to the mixture. The mixture was filtered, and the filtrate was washed with H2O (35 mL x 3). The organic layer was separated, dried over Na2SO4, and then vacuum distilled.A yellow residue was obtained. The residue was purified by silica gel column chromatography using 20-50% petroleum ether / ethyl acetate to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide, which was a brown solid. TLC; 5% MeOH / DCM (Rf: 0.2). MS calculation: C19H17ClFN3O2: 373.13. Measured: 374.1 [M+1]+.

[0320] Alternative synthesis of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide. To a solution of 4-bromo-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-methylamide (13.3 g, 40.0 mmol) in 1,4-dioxane / H₂O (v / v = 7:1, 120 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one (12.2 g, 48.0 mmol), Pd(dppf)Cl₂ (2.9 g, 4.0 mmol), and Na₂CO₃ (10.6 g, 100.0 mmol) were added. The mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The solid was washed with EA, and the filtrate was concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography using 5% methanol / DCM (120 g silica gel column, 60 mL / min) to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (12.8 g, 85.6%), a brown solid. TLC: 7% methanol / DCM (Rf: 0.5); MS calculation: C19H17ClFN3O2: 373.1; Measured: 374.3 [M+1]+.

[0321] Example 1

[0322]

[0323] N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-octahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide. Pd / C (30 mg, 10% Pd) was added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (300 mg, 0.8 mmol) in THF (20 ml).The mixture was stirred at 30°C for 5 hours under H2. The mixture was filtered, and the filtrate was evaporated under vacuum to give a yellow residue. The residue was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide, a brown solid as a single diastereomer. TLC; 50% ethyl acetate / petroleum ether (Rf: 0.3). MS calculation: C19H19ClFN3O2: 375.2; actual: 376.2 [M+1]+.

[0324] Alternative Synthesis of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide

[0325] Pd / C (6.4 g, 10%) was added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (12.8 g, 34.2 mmol) in THF (200 mL) under H2, and the mixture was stirred at room temperature for 4 hours. The mixture was filtered through a diatomaceous earth mat and washed with methanol. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by silica gel column chromatography with 5% methanol / DCM (80 g silica gel column, 50 mL / min) to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide, a gray solid, as a single diastereomer (12.0 g, 93.3%). TLC: 7% methanol / DCM (Rf: 0.5); MS calculation: C19H19ClFN3O2: 375.2; MS determination: 376.3 [M+1]+.

[0326] Example 2

[0327]

[0328] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, specification 33 / 163 pages 36 CN 121248511 A. NaBH4 (36 mg, 0.95 mmol) was added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (20 mg, 0.053 mmol) in MeOH (2 ml). The mixture was stirred at room temperature for 8 hours. The mixture was then evaporated under vacuum to give a yellow residue. The residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, a white solid, as a mono-...One diastereomer. TLC; 50% ethyl acetate / petroleum ether (Rf: 0.3). MS calculation: C19H21ClFN3O2: 377.1. Measured: 378.2 [M+1]+. 1H NMR (DMSO‑d6, 400MHz): δ10.22(s,1H) ,7.96(dd ,J=6.8,2.4Hz,1H) ,7.64 (s ,1H) ,7.58‑7.54(m ,1H) ,7.40(t,J=8.8Hz,1H) ,4.50(d ,J=4.4Hz,1H) ,4.03(dd ,J=6.8,2.4Hz ,1H) ,3.66(s ,3H) ,3.26‑3.20(m ,1H) ,2.32‑2.28(m ,2H) ,2.11‑2.05(m ,2H) , 1.95-1.89(m,2H) ,1.70-1.62 (m, 2H) ,1.30-1.23 (m, 2H) ppm.

[0329] Example 3

[0330]

[0331] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((methanesulfonyl)methyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. n-BuLi (0.2 mL, 0.5 mmol) was added to a solution of methanesulfonylmethane (24 mg, 0.26 mmol) in THF (5 mL) at -78 °C. The solution was stirred at -78 °C for 30 minutes. N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazolium-5-carboxamide (50 mg, 0.13 mmol) was then added, and the reaction was slowly heated to room temperature and stirred for 5 hours. The reaction mixture was quenched with H₂O (20 mL) and extracted with ethyl acetate. The organic layer was concentrated under vacuum, and the residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-((methanesulfonyl)methyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazolium-5-carboxamide, a white solid, as a single diastereomer. TLC; 20% ethyl acetate / petroleum ether (Rf: 0.4). MS calculation: C21H25ClFN3O4S: 469.1; Measured: 470.2 [M+1]+; 1H NMR (DMSO-d6, 400MHz): δ 10.22 (s, 1H), 7.96 (dd, J = 6.8, 2.4Hz, 1H), 7.64 (s, 1H), 7.59–7.55 (m, 1H), 7.41 (t, J = 9.2Hz, 1H), 4.94 (s, 1H), 3.66 (s, 3H), 3.24–3.19 (m, 3H),2.97(s,3H),2.49-2.44(m,2H),2.08-2.01(m,4H),1.78-1.75(m,2H),1.61 (dd,J=13.2,4.0Hz,2H)ppm.

[0332] Example 4

[0333]

[0334] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-formamide. Add a solution of i-PrMgCl in THF (2.0 M, 0.5 mL, 1.0 mmol) to a solution of 4-iodo-1-methyl-1H-imidazole (208 mg, 1.0 mmol) in THF (5 mL). Stir the mixture at room temperature for 2 hours. Add a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazole in THF (46 mg, 0.08 mmol). Stir the final mixture at room temperature overnight. Quench the reaction mixture with methanol (2.0 mL) and concentrate under vacuum. The residue was purified by preparative HPLC to provide N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, a white solid, as a single diastereomer. MS calculation: C23H25ClFN5O2: 457.2; Found: 458.3 [M+1]+. 1H NMR(DMSO‑d6,400MHz):10.20(s,1H),7.95(dd,J=6.8,2.4Hz,1H),7.64(s,1H),7.54‑7.58(m,1H),7.38‑7.42(m,2H),6.87(s,1H) ,4.53(s,1H) ,3.67(s,3H) ,3.57(s,3H) ,3.16‑ 3.24(m,1H) ,2.40‑2.49(m,2H) ,2.17‑2.22(m,2H) ,2.02‑2.08(m,2H) ,1.85‑1.93(m,2H) , 1.59–1.63 (m, 2H) ppm.

[0335] Example 5

[0336]

[0337] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-2-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. To 1-methyl-1H-imidazolium (82 mg)A solution of n-BuLi in hexane (2.5 M, 0.4 mL, 1.0 mmol) was added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (46 mg, 0.08 mmol) in THF (2.0 mL). The final mixture was stirred overnight at room temperature. The reaction mixture was quenched with methanol (2.0 mL) and concentrated under vacuum. The residue was purified by preparative HPLC to provide N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazolium-2-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazolium-5-carboxamide, a white solid, as a single diastereomer. MS calculation: C23H25ClFN5O2: 457.2; Measured: 458.3 [M+1]+; 1H NMR (CD3OD, 400MHz): 7.87 (dd, J = 6.4, 2.4Hz, 1H), 7.65 (s, 1H), 7.52–7.48 (m, 1H), 7.23 (t, J = 8.8Hz, 1H), 6.98 (d, J = 1.2Hz, 1H), 6.76 (d, J = 1.2Hz, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.30–3.35 (m, 1H), 2.56–2.58 (m, 4H), 2.22–2.25 (m, 2H) ,1.83-1.93(m,4H)ppm.

[0338] Synthesis of Examples 6 to 15. Examples 6 to 15 in Table 1 were synthesized using the corresponding starting materials according to the procedures provided above.

[0339] Table 1. Examples 6 to 15 Specification 35 / 163 pages 38 CN 121248511 A

[0340] Specification 36 / 163 pages 39 CN 121248511 A

[0341] Specification 37 / 163 pages 40 CN 121248511 A

[0342] Specification 38 / 163 pages 41 CN 121248511 A

[0343] Specification 39 / 163 pages 42 CN 121248511 A

[0344]

[0345] Intermediate 8 Specification 40 / 163 pages 43 CN 121248511 A

[0346]

[0347] 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)hexahydrocyclopentadieneEthyl 2-(1H)-ethylene-2(1H)-ethylene(ethylene)-2-(diethoxyphosphono)ethyl acetate. NaH (48 mg, 2 mmol) was slowly added to a solution of ethyl 2-(diethoxyphosphono)ethyl acetate (448 mg, 2 mmol) in dry THF (25 mL), followed by stirring at 0 °C for 0.5 h. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (375 mg, 1 mmol) was added to THF (5 mL), and stirring was continued at room temperature for 3 h. Water was added, and the pH was adjusted to 6–7 with NH4Cl. The mixture was extracted with AcOEt, the organic phase was dried, and concentrated under vacuum. The residue was purified by column chromatography using 25-60% ethyl acetate / petroleum ether to give ethyl acetate 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)hexahydrocyclopentadien-2(1H)-ylidene)ethyl acetate, a pale yellow solid. TLC; 60% ethyl acetate / petroleum ether (Rf: 0.2). MS calculation: C23H25ClFN3O3: 445.2; actual: 446.3 [M+1]+.

[0348] Example 16

[0349]

[0350] ethyl acetate 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)ethyl acetate. Pd / C (50 mg) was added to a solution of ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)hexahydrocyclopentadien-2(1H)-ylidene)ethyl acetate (223 mg, 0.5 mmol) in THF (15 mL). The flask was then emptied and backfilled with H2. The solution was stirred overnight at room temperature. The mixture was filtered and concentrated. The residue was purified by preparative HPLC to give ethyl 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)ethyl acetate, a white solid. TLC: 60% ethyl acetate / petroleum ether (Rf: 0.2). MS calculation: C23H27ClFN3O3: 447.2. Found: 448.3 [M+1]+.

[0351] Intermediate 9 Specification 41 / 163 pages 44 CN 121248511 A

[0352]

[0353] 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)acetic acid. To 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)acetic acid (45 mg, 0LiOH (42 mg, 1 mmol) was added to a solution of CH3OH / H2O (5 mL / 1 mL). The solution was stirred at room temperature for 4 hours. Water was added, and the reaction mixture was adjusted to pH 5-6 with HCl (2 M). The reaction was extracted with ethyl acetate (10 mL × 3), the organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to give crude 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)acetic acid, which was a pale yellow solid. TLC; 100% ethyl acetate / petroleum ether (Rf: 0.1). MS calculation C21H23ClFN3O3: 419.1; Found: 420.2 [M+1]+.

[0354] Example 17

[0355]

[0356] 4-(5-(2-amino-2-oxoethyl)octahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. NH4Cl (54 mg, 1 mmol), HATU (38 mg, 0.1 mmol), and Et3N (101 mg, 1 mmol) were added to a solution of 2-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)octahydrocyclopentadien-2-yl)acetic acid (43 mg, 0.1 mmol) in anhydrous DCM (10 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was removed, and the crude product was purified by preparative HPLC to give 4-(5-(2-amino-2-oxoethyl)octahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide, a white solid. TLC: 80% ethyl acetate / petroleum ether (Rf: 0.3). MS calculation: C21H24ClFN4O2: 418.2; Measured: 419.3 [M+1]+. 1H NMR (DMSO‑d6, 400MHz): δ10.21(s,1H) ,7.95(dd,J=7.2,2.4Hz,1H) ,7.65(s,1H) ,7.58‑7.55(m,1H) ,7.40 (t,J=9.2Hz,1H) ,7.19(s,1H) ,6.65(s,1H) ,3.66(s,3H) ,3.34‑3.32(m,1H) ,2.43‑2.36(m, 2H) ,2.21‑2.18(m,1H) ,2.10‑2.06(m,4H) ,1.99‑1.92(m,2H) ,1.50-1.47(m,2H) 0.93–0.90 (m, 2H)ppm.

[0357] Example 18 Specification 42 / 163 pages 45 CN 121248511 A

[0358]

[0359] N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-(4-methylpiperazin-1-yl)octahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. 1-methylpiperazine (110 mg, 1.1 mmol) and NaBH3CN (40 mg, 0.65 mmol) were added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (50 mg, 0.13 mmol) in THF (3 ml). The mixture was stirred overnight at 55 °C. The solvent was removed under vacuum to obtain a yellow residue. It was purified by column chromatography and preparative HPLC to give N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-(4-methylpiperazin-1-yl)octahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide, which was a white solid. TLC: 10% DCM / MeOH (Rf: 0.3). MS calculation: C24H31ClFN5O: 459.2; Measured: 460.3 [M+1]+; 1H NMR (DMSO-d6, 400MHz): δ 10.23 (s, 1H), 7.95 (dd, J=6.8, 2.4Hz, 1H), δ 7.66 (s, 1H), 7.59–7.55 (m, 1H), 7.41 (t, J=9.2Hz, 1H), 3.67 (s, 3H), 3.25 (s, 1H), 2.49 (s, 1H), 3.36–3.30 (m, 9H), 2.18–2.00 (m, 8H), 1.58–1.50 (m, 2H) ,1.17-1.09 (m, 2H) ppm.

[0360] Intermediate 10

[0361]

[0362] N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1'H-spiro[ethylene oxide-2,2'-cyclopentadienyl]-5'-yl)-1-methyl-1H-imidazolium-5-carboxamide. Trimethylsulfonium iodide (1.47 g, 6.7 mmol) was added to a solution of t-BuOK (0.75 g, 6.7 mmol) in THF (20 mL). The mixture was stirred at room temperature for 1 hour. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadienyl-2-yl)-1H-imidazolium-5-carboxamide (0.5 g, 1.3 mmol) was added, and the mixture was heated to 60 °C and maintained for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (2:1) to give N-(3-chloro-4-fluorophenyl)-4-(hexachloro ...Hydrogen-1'H-spiro[ethylene oxide-2,2'-cyclopentadiene]-5'-yl)-1-methyl-1H-imidazolium-5-carboxamide, which is a white solid. TLC; 50% ethyl acetate / petroleum ether (Rf: 0.2). MS calculation: C20H21ClFN3O2: 389.1; actual: 390.2 [M+1]+.

[0363] Example 19 Specification 43 / 163 pages 46 CN 121248511 A

[0364]

[0365] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-cyclopentadiene-2-yl)-1-methyl-1H-imidazolium-5-carboxamide isomer I. H₂SO₄ (0.1 mL) was added to a solution of N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1'H-spiro[ethylene oxide-2,2'-cyclopentadienyl]-5'-yl)-1-methyl-1H-imidazolium-5-carboxamide (100 mg, 0.26 mmol) in THF / H₂O (6:1, 5 mL), and the mixture was stirred overnight at room temperature. The reaction was alkalized with NaHCO₃ (aqueous solution) and then extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by preparative HPLC to give isomer I of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-cyclopentadienyl-2-yl)-1-methyl-1H-imidazolium-5-carboxamide, which was a white solid. TLC; 5% MeOH / DCM (Rf: 0.4). MS calculation: C20H23ClFN3O3: 407.1; Measured: 408.2 [M+1]+; 1H NMR (DMSO-d6, 400MHz): δ

[0366] 10.21(s,1H), 7.96(dd,J=7.2,2.8Hz,1H), 7.65(s,1H), 7.59-7.55(m,1H), 7.41 (t,J=8.8Hz,1H), 4.54(t,J=5.6Hz,1H), 4.02(s,1H), 3.67(s,3H), 3.30(s,1H), 3.25(d,J =5.6Hz,2H), 2.65-2.58(m,2H) ,2.10-2.03 (m, 2H), 1.65-1.60 (m, 2H), 1.52-1.42 (m, 4H) ppm.

[0367] Example 20

[0368]

[0369] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-2-cyclopentadien-1-methyl-1H-imidazol-5-carboxamide isomer II. To N-(3-chloro-4-fluorophenyl)-4-(hexahydro-1H-spiro[ethylene oxide-2,2'-cyclopentadien]-51-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-2-cyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (100 mg, 0.26 mmol) was dissolved in dioxane (2 mL) and water (0.5 mL) and then mixed with NaOH (80 mg, 2.0 mmol). The mixture was stirred at 100 °C for 24 hours. After cooling, the pH was adjusted to 8 with 1 N HCl and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(hydroxymethyl)octahydro-2-cyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide isomer II, which was a pale yellow solid. TLC; 5% MeOH / DCM (Rf: 0.4). MS calculation: C20H23ClFN3O3: 407.1; Measured: 408.2 [M+1]+; 1H NMR (DMSO-d6, 400MHz): δ 10.21 (s, 1H), 7.96 (dd, J = 7.2, 2.8Hz, 1H), 7.64 (s, 1H), 7.58–7.55 (m, 1H), 7.41 (t, J = 8.8Hz, 1H), 4.45 (t, J = 5.6Hz, 1H), 4.14 (s, 1H), 3.67 (s, 3H), 3.23–3.19 (m, 3H), 2.36–2.33 (m, 2H), 2.07–2.04 (m, 2H) ,1.89-1.84(m,2H) ,1.81-1.74(m,2H) ,1.33(dd,J=13.2,4.4Hz,2H)ppm.

[0370] Example 21 Specification 44 / 163 Page 47 CN 121248511 A

[0371]

[0372] 2-chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-formamide. NCS (700 mg, 5.3 mmol) and AIBN (0.25 g, 1.5 mmol) were added to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (200 mg, 0.53 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred overnight at 35 °C. The mixture was evaporated under vacuum to give a yellow residue. The residue was purified by silica gel column chromatography to give 2-chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide, a yellow solid. TLC: 40% ethyl acetate / petroleum ether (Rf: 0.3). MS calculationsThe concentration was: C19H18Cl2FN3O2: 409.1, measured: 410.2 [M+1]+.

[0373] Example 22

[0374]

[0375] 2-chloro-N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazolium-5-carboxamide. NaBH4 (36 mg, 0.95 mmol) was added to a solution of 2-chloro-N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (20 mg, 0.05 mmol) in MeOH (2 ml). The mixture was stirred at room temperature for 8 hours. The solvent was evaporated under vacuum to give a yellow residue. The residue was purified by preparative HPLC to give 2-chloro-N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazolium-5-carboxamide, a white solid. TLC; 50% ethyl acetate / petroleum ether (Rf: 0.3). MS calculation: C19H20Cl2FN3O2: 411.1; Measured: 412.2 [M+1]+; 1H NMR (DMSO-d6, 400MHz): δ 10.39 (s, 1H), 7.95 (dd, J = 6.8, 4.8Hz, 1H), 7.57–7.54 (m, 1H), 7.42 (t, J = 9.2Hz, 1H), 4.51 (d, J = 4.0Hz, 1H), 4.05 (dd, J = 11.2, 6.8Hz, 1H), 3.61 (s, 3H), 3.22–3.16 (m, 1H), 2.36–2.20 (m, 2H), 2.10–2.04 (m, 2H) ,1.93-1.86(m,2H), 1.69-1.61(m,2H), 1.33-1.26(m,2H)ppm.

[0376] Intermediate 11

[0377]

[0378] 2-Methyl-1H-imidazolium-4,5-dicarboxynitrile. A solution of 2,3-diaminocis-butenonitrile (54 g, 0.5 mol) and CH3C(OEt)3 (9.6 g, 0.8 mmol) in xylene (200 mL) was stirred at 130 °C for 6 hours. After cooling to room temperature, it was filtered to give 2-methyl-1H-imidazolium-4,5-dicarboxynitrile as a brown solid. TLC; 30% ethyl acetate / petroleum ether (Rf: 0.4). MS calculation: C6H4N4: 132.0. Actual: 133.0 [M+1]+. Instructions for Use, Page 45 / 163, CN 121248511 A

[0379] Intermediate 12

[0380]

[0381] 1,2-Dimethyl-1H-imidazolium-4,5-dicarboxynitrile. At 55°C, 1,2-dimethyl-1H-imidazolium-4,5-dicarboxynitrile was reacted with 1,2-dimethyl-1H-imidazolium-4,5-dicarboxynitrile.5-Dimethyl nitrile (50 g, 0.38 mol) and NaHCO3 (160 g, 1.51 mol) were added dropwise to a suspension in H2O (300 mL) with dimethyl sulfate (62 g, 0.49 mol) and the reaction was stirred at the same temperature for 6 hours. Ice water was added and the mixture was extracted with ethyl acetate (300 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give 1,2-dimethyl-1H-imidazolium-4,5-dimethyl nitrile, which could be used in the next step without further purification. TLC; 30% ethyl acetate / petroleum ether (Rf: 0.5). MS calculation: C7H7N4: 146.0; actual: 147.0 [M+1]+.

[0382] Intermediate 13

[0383]

[0384] 1,2-Dimethyl-1H-imidazolium-4,5-dicarboxylic acid. A solution of 1,2-dimethyl-1H-imidazolium-4,5-dicarboxynitrile (41 g, 0.28 mol) in 2M NaOH aqueous solution (45 g, 1.12 mol, 560 mL) was stirred at 100 °C for 6 hours. After cooling to room temperature, the solution was acidified with 6N HCl aqueous solution (pH = 1). After filtration, the solid was dried in an oven at 100 °C for 16 hours to obtain 1,2-dimethyl-1H-imidazolium-4,5-dicarboxylic acid, which was a white solid. MS calculation: C7H8N2O4: 184.0. Actual measurement: 185.1 [M+ 1]+.

[0385] Intermediate 14

[0386]

[0387] 1,2-dimethyl-1H-imidazolium-5-carboxylic acid. A suspension of 1,2-dimethyl-1H-imidazolium-4,5-dicarboxylic acid (5 g, 27 mmol) in Ac2O (150 mL) was stirred at 100 °C for 16 hours. The reaction was concentrated to give a crude product, which was crystallized from acetone (100 mL) to give 1,2-dimethyl-1H-imidazolium-5-carboxylic acid, a brown solid. MS calculation: C6H8N2O2: 140.1; Actual: 141.1 [M+1]+.

[0388] Intermediate 15

[0389]

[0390] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazolium-5-carboxamide. HATU (2.28 g, 6 mmol) was added to a solution of 2-dimethyl-1H-imidazolium-5-carboxylic acid (560 mg, 4 mmol), 3-chloro-4-fluoroaniline (870 mg, 6 mmol), and DIEA (1.03 g, 8 mmol) in THF / DMF (15 mL / 3 mL), and the reaction was stirred at room temperature for 16 hours. Ice water was added and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated to obtain the crude product. This crude product was then subjected to…Purification was performed by silica gel column chromatography using ethyl acetate / MeOH = 10:1 to give N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazol-5-carboxamide, which is a white solid. TLC: 10% ethyl acetate / MeOH (R f: 0.4). MS calculation: 267.1; Actual result: 268.1 [M+1]+.

[0391] Intermediate 16

[0392]

[0393] 4-bromo-N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazol-5-carboxamide. Br2 (1.5 g, 9.6 mmol) was added dropwise to a suspension of N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazolium-5-carboxamide (510 mg, 1.91 mmol) and NaOAc (1.57 g, 19.1 mmol) in EtOH (40 mL) at 15 °C. The reaction mixture was then stirred at room temperature for 11 hours. The reaction was quenched with 0.5% NaHSO3 (aqueous solution) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a residue, which was purified by silica gel column chromatography using ethyl acetate / MeOH = 10:1 to give 4-bromo-N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazolium-5-carboxamide, a white solid. TLC: 10% ethyl acetate / MeOH (Rf: 0.6). MS calculation: C12H10BrClFN3O: 345.0; Actual measurement: 346.2 [M+1]+.

[0394] Intermediate 17

[0395]

[0396] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. Pd(dppf)Cl2 (50 mg) was added to a solution of 4-bromo-N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-1H-imidazolium-5-carboxamide (400 mg, 1.16 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one (431 mg, 1.74 mmol) and Na2CO3 (246 mg, 2.32 mmol) in a mixture of dioxane (20 mL) and H2O (5 mL) under a nitrogen atmosphere. The reaction was stirred at 80 °C for 6 hours. After cooling to room temperature, the mixture was filtered through a filter pad. The filtrate was diluted with water and extracted with ethyl acetate (40 mL x 2).The organic layer was concentrated to obtain the residue, which was purified by silica gel column chromatography using ethyl acetate / MeOH = 10:1 to give N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide, a white solid. TLC: 10% ethyl acetate / MeOH (Rf: 0.3). MS calculation: C20H19ClFN3O2: 387.1. Actual: 388.2 [M+1]+.

[0397] Example 23

[0398] Specification 47 / 163 pages 50 CN 121248511 A

[0399] N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-octahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. A mixture of N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (300 mg, 0.77 mmol) and Pd / C (300 mg) was stirred in ethyl acetate (300 ml) at 30 °C for 6 hours under H2. The reaction mixture was cooled to room temperature and filtered through a 545 pad, washed with ethyl acetate and concentrated to give a crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide, a white solid. TLC: 10% ethyl acetate / CH3OH (Rf: 0.5). MS calculation: C20H21ClFN3O2: 589.2; actual: 390.2 [M+1]+.

[0400] Example 24

[0401]

[0402] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1,2-dimethyl-1H-imidazolium-5-carboxamide. NaBH4 (11 mg, 0.27 mmol) was added to a solution of N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (35 mg, 0.09 mmol) in MeOH (2 mL) cooled to 0 °C. The reaction was stirred at room temperature for 1 hour. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was concentrated to give a crude compound, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxyoctahydrocyclopentadien-2-yl)-1,2-dimethyl-1H-imidazol-5-carboxamide, a white solid. TLC: 10% ethyl acetate / CH3OH (Rf: 0.4). MS calculation: C20H23ClFN3O2: 391.1; Measured: 392.1 [M+1]+; 1H NMR (CD3OD, 400MHz): δ 7.86 (dd, J = 2.4Hz, 6.4Hz, 1H), 7.52-7.46 (m, 1H), 7.23 (t, J = 8.8Hz, 1H), 4.17-4.10 (m, 1H), 3.63 (s, 3H), 3.32-3.20 (m, 1H), 2.40-2.38 (m, 5H), 2.24-2.01 (m, 4H), 1.75-1.62 (m, 2H), 1.41-1.37 (m, 2H)ppm.

[0403] Synthesis of Examples 25 to 26. Synthesize Examples 25 to 26 in Table 2 using the corresponding starting materials according to the procedures provided above.

[0404] Table 2. Examples 25 to 26 Specification 48 / 163 pages 51 CN 121248511 A

[0405]

[0406] Example 27

[0407]

[0408] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazol-2-yl)octahydrocyclopentadien-2-yl)-1,2-dimethyl-1H-imidazol-5-carboxamide. Add n-BuLi (2.5M, 0.5mL, 1.25mmol) in hexane to a solution of 1-methyl-1H-imidazolium (101mg, 1.23mmol) in THF at -78°C. Specification 49 / 163 pages 52 CN 121248511 A (2mL) The reaction was stirred at -78°C for 1 hour. N,N-(3-chloro-4-fluorophenyl)-1,2-dimethyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (60 mg, 0.154 mmol) was added to the solution in a single addition. The reaction was stirred at -78°C for 1 hour, then allowed to warm to room temperature overnight. The mixture was quenched with methanol (2.0 mL) and concentrated under vacuum. The residue was purified by preparative HPLC to provide N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-1H-imidazolium-2-yl)octahydrocyclopentadien-2-yl)-1,2-dimethyl-1H-imidazolium-5-carboxamide, a white solid, as a single diastereomer. MS calculation: C24H27ClFN5O2: 471.1; Measured: 472.3 [M+1]+; 1H NMR (DMSO-d6, 400MHz): δ 10.10 (s, 1H), 7.95 (dd, J = 6.8, 2.8Hz, 1H), 7.57–7.53 (m, 1H), 7.39 (t, J = 9.2Hz, 1H), 7.00 (s, 1H), 6.65 (s, 1H), 5.23 (s, 1H), 3.73 (s, 3H),3.55(s, 3H),3.21-3.18(m, 1H),2.43-2.41(m, 4H),2.31(s, 1H),2.06-2.03(m, 2H),1.82-1.77(m, 4H)ppm.

[0409] Synthesis of Examples 28 to 30. Examples 28 to 30 in Table 3 were synthesized using the corresponding starting materials according to the procedures provided above.

[0410] Table 3. Examples 28 to 30 Specification 50 / 163 pages 53 CN 121248511 A

[0411] Specification 51 / 163 pages 54 CN 121248511 A

[0412]

[0413] Intermediate 18

[0414]

[0415] 2-Bromo-N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide. A solution of 2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxylic acid (500 mg, 2.2 mmol) in SOCl2 (6 mL) was stirred at 80 °C for 4 hours. The reaction was concentrated to remove volatiles. The residue was dissolved in anhydrous DCM (5 mL). 3-Chloro-4-fluoroaniline (473 mg, 3.3 mmol) and Et3N (440 mg, 4.4 mmol) were added. The reaction was stirred at room temperature for 1 hour, followed by concentration to remove the solvent. The residue was diluted with ethyl acetate and washed with brine. The ethyl acetate solution was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (40 g silica gel column, eluted with petroleum ether / ethyl acetate) to give 2-bromo-N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide, a brown solid. TLC; 50%, ethyl acetate / petroleum ether (Rf: 0.3). MS calculation: C13H10BrClFN3O: 357.0; actual: 357.9 [M+1]+.

[0416] Intermediate 19

[0417]

[0418] N-(3-chloro-4-fluorophenyl)-2-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-6,7-dihydrocyclopentadien-2-yl)-6,7-dihydrocyclopentadien-2-yl)-6,7-dihydrocyclopentadien-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl))) To 2-bromo-N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide (660 mg, 1.9 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,6,6a-tetrahydrocyclopentadien-2(1H)-one (4.0 g, 15% purity, 2Pd(dppf)Cl2 (95 mg, 0.13 mmol) was added to a solution of dioxane (15 mL) and K3PO4 (785 mg, 3.7 mmol) in H2O (3 mL). The reaction was carried out overnight at 80 °C under a nitrogen atmosphere with stirring. Volatiles were removed under vacuum, and the residue was purified by silica gel column chromatography (40 g silica gel column, eluted with petroleum ether / ethyl acetate) to give N-(3-chloro-4-fluorophenyl)-2-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide, a white solid. TLC: 70% ethyl acetate / petroleum ether (Rf: 0.2). MS calculation: C21H19ClFN3O2: 399.1; Actual measurement: 400.3 [M+1]+.

[0419] Example 31

[0420]

[0421] N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide. Pd / C (100 mg, 100% w / w) was added to a solution of N-(3-chloro-4-fluorophenyl)-2-(5-oxo-1,3a,4,5,6,6a-hexahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide (100 mg, 0.3 mmol) in ethyl acetate (25 mL), and the reaction solution was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was then filtered, and the filtrate was concentrated to give a crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide, a white solid. TLC: 10% MeOH / DCM (Rf: 0.6). MS calculation: C21H21ClFN3O2: 401.1; Actual measurement: 402.2 [M+1]+. 1H NMR (CD3OD, 400MHz): δ 7.83 (dd, J = 6.8, 2.8Hz, 1H), 7.51–7.47 (m, 1H), 7.23 (t, J = 9.2Hz, 1H), 4.16 (t, J = 7.2Hz, 2H), 3.64–3.55 (m, 1H), 2.88–2.78 (m, 3H), 2.66–2.58 (m, 2H), 2.56–2.49 (m, 2H), 2.39–2.32 (m, 2H), 2.25–2.19 (m, 2H), 1.75–1.67 (m, 4H) ppm.

[0422] Example 32

[0423]

[0424] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide isomers I and II. NaBH4 (11 mg, 0.3 mmol) was added to a solution of N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide (60 mg, 0.2 mmol) in MeOH (5 mL), and the solution was stirred at room temperature for 3 hours. After the starting material was exhausted, the volatiles were removed under vacuum, and the residue was purified by preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide isomers I and II. Specification 53 / 163 pages 56 CN 121248511 A

[0425] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide isomer I. MS calculation: C21H23ClFN3O2: 403.1; Measured: 404.2 [M+1]+; 1H NMR (CD3OD, 400MHz): δ 7.82 (dd, J = 6.8, 2.8Hz, 1H), 7.49–7.45 (m, 1H), 7.22 (t, J = 9.2Hz, 1H), 4.45–4.42 (m, 1H), 4.15 (t, J = 7.2Hz, 2H), 3.38–3.31 (m, 1H), 2.87–2.84 (m, 2H), 2.66–2.58 (m, 4H), 2.23–2.16 (m, 2H), 1.71–1.68 (m, 4H) ,1.56-1.48(m,2H)ppm.

[0426] Example 33

[0427]

[0428] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxyoctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide isomer II. MS calculation: C21H23ClFN3O2: 403.1; Measured: 404.2 [M+1]+; 1H NMR (CD3OD, 400MHz): δ 7.82 (dd, J=6.8, 2.8Hz, 1H), 7.49-7.45 (m, 1H), 7.22 (t, J=8.8Hz, 1H), 4.18-4.14 (m, 3H), 3.48-3.42 (m, 1H), 2.88-2.84 (m, 2H), 2.66-2.60 (m, 2H), 2.48-2.46 (m, 2H),2.26-2.19(m,2H) ,2.15-2.09(m,2H) ,1.77-1.69(m,2H) ,1.45-1.38(m,2H)ppm.

[0429] Example 34

[0430]

[0431] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-(trifluoromethyl)octahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide (100 mg, 0.25 mmol) in THF (2 mL), TBAF (0.75 mL (1 M), 0.75 mmol) and TMSCF3 (213 mg, 1.5 mmol) were added, and the mixture was stirred overnight at 60 °C. After cooling to room temperature, another batch of TMSCF3 (213 mg, 1.5 mmol) was added, and stirring was continued at 60 °C for 6 hours. After cooling to room temperature, another batch of TMSCF3 (213 mg, 1.5 mmol) was added, and stirring was continued overnight at 60 °C. After the starting material was completely exhausted, the reaction was concentrated. The residue was diluted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give a crude compound, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-(trifluoromethyl)octahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide, a white solid as a single diastereomer. TLC: 5% MeOH / DCM (Rf: 0.4). MS calculation: C22H22ClF4N3O2: 471.1; Measured: 472.2 [M+1]+; 1H NMR (CD3OD, 400MHz): δ 7.83 (dd, J = 6.8, 2.8Hz, 1H), 7.49–7.45 (m, 1H), 7.22 (t, J = 9.2Hz, 1H), 4.16 (t, J = 7.2Hz, 2H), 3.43–3.38 (m, 1H), 2.86 (t, J = 7.2Hz, 2H), 2.74–2.72 (m, 2H), 2.66–2.60 (m, 2H), 2.26–2.14 (m, 4H), 1.98–1.90 (m, 2H), 1.79 (dd, J = 6.8, 2.8Hz, 1H), 4.82 (m, 2 ... (J = 13.6 Hz, 2H) ppm. Specification 54 / 163 pages 57 CN 121248511 A

[0432] Example 35

[0433]

[0434] N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-((methanesulfonyl)methyl)octahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide. n-BuLi (0.32 mL, 0.8 mmol) was added to a solution of dimethyl sulfoxide (75 mg, 0.8 mmol) in 1 mL of THF at -78 °C under a nitrogen atmosphere, and the reaction was stirred at -78 °C for 1 hour. N-(3-chloro-4-fluorophenyl)-2-(5-oxooctahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide (40 mg, 0.1 mmol) was added to 1 mL of THF at -78 °C, and the reaction was stirred at -78 °C for 30 minutes. The reaction was then heated to room temperature and stirred for 2 hours. The reaction was quenched with water and concentrated. The residue was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-2-(5-hydroxy-5-((methanesulfonyl)methyl)octahydrocyclopentadien-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-3-carboxamide, a white solid as a single diastereomer. TLC: 5% MeOH / DCM (Rf: 0.4). MS calculation: Chemical formula: C23H27ClFN3O4S: 495.1; Measured: 496.2 [M+1]+; 1H NMR (DMSO-d6, 400MHz): δ 9.74 (s, 1H), 7.91 (dd, J = 6.8, 2.4Hz, 1H), 7.57–7.53 (m, 1H), 7.39 (t, J = 8.8Hz, 1H), 4.96 (s, 1H), 4.08 (t, J = 7.2Hz, 2H), 3.39–3.33 (m, 1H), 3.26 (s, 2H), 2.99 (s, 3H), 2.75 (t, J = 7.2Hz, 2H), 2.54–2.47 (m, 4H) ,2.08-2.03 (m, 4H), 1.86-1.78 (m, 2H), 1.65-1.61 (m, 2H) ppm.

[0435] Synthesis of Examples 36 to 49. Examples 36 to 49 in Table 4 were synthesized using the corresponding starting materials according to the procedure provided above.

[0436] Table 4. Examples 36 to 49 Specification 55 / 163 pages 58 CN 121248511 A

[0437] Specification 56 / 163 pages 59 CN 121248511 A

[0438] Specification 57 / 163 pages 60 CN 121248511 A

[0439] Specification 58 / 163 pages 61 CN 121248511 A

[0440] Specification 59 / 163 pages62 CN 121248511 A

[0441]

[0442] General procedure for alkylation, method A

[0443] K2CO3 (2 equivalents) and KI (0.5 equivalents) were added to a stirred solution of Ar-OH (1 equivalent) and the halogenated compound (2 equivalents) in acetonitrile / DMF (4 mL / mmol). The reaction mixture was stirred at 60°C to 80°C for 12-16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude compound, which was purified by silica gel column chromatography or preparative HPLC to obtain the desired compound.

[0444] General method for alkylation, method B

[0445] Cs2CO3 (2.5 equivalents) was added to a stirred solution of Ar-OH (1 equivalent) and the halogenated compound (2 equivalents) in DMF / ACN (6 mL / mmol). The reaction mixture was stirred at room temperature / 60°C for 2 to 4 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude compound, which was purified by silica gel column chromatography or preparative HPLC to obtain the desired compound.

[0446] Intermediate 20

[0447]

[0448] 1-Methyl-3-nitro-1H-pyrazole. NaOtBu (19.11 g, 199.1 mmol) was added to a stirred solution of 3-nitro-1H-pyrazole (15 g, 132.7 mmol) in DMF (150 mL) at 0°C, and the reaction was stirred for 20 minutes. MeI (9.91 mL, 159.24 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 1-methyl-3-nitro-1H-pyrazole (10 g, 59%) as a creamy white solid. TLC: 20% EtOAc / hexane (Rf: 0.2). 1H NMR (400 MHz, DMSO-d6): δ 7.98 (s, 1H), 7.03 (d, J = 2.0 Hz, 1H), 3.97 (s, 3H) ppm.

[0449] Example 50

[0450]

[0451] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazole-5-yl)octahydrocyclopentanolDien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. LDA (2 M in THF, 60 mL, 120 mmol) was added dropwise to a stirred solution of methyl-3-nitro-1H-pyrazole (10.16 g, 80 mmol) in 100 mL of dry THF at -78 °C under an inert atmosphere, and the reaction mixture was stirred for 2 hours. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (3 g, 8 mmol) in THF was added to the mixture at -78 °C. The resulting reaction mixture was stirred at -78 °C for 1 hour. The reaction progress was monitored by TLC and LCMC. After completion, the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (2 g, 50%), which was an off-white solid. TLC: 5% MeOH / DCM (Rf: 0.3). 1H‑NMR (DMSO‑d6, 400MHz): δ10.23(s,1H), 7.96(dd,J=6.8Hz,2.4Hz,1H), 7.66(s,1H), 7.59‑7.55(m,1H), 7.40(t,J=9.2Hz,1H), 6.93(s,1H) ,5.60(s,1H) ,4.05(s,3H) ,3.68(s,3H) ,3.29‑3.24(m,1H) ,2.51‑2.49(m,2H) , 2 .30‑2 .24(m ,2H) ,2 .13‑2 .07(m ,2H) ,1 .94‑1 .85 (m, 4H) ppm; MS calculation: C23H24ClFN6O4: 502.2; Actual measurement: 503.3 [M+1]+.

[0452] Example 51

[0453]

[0454] 4-(5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. 10% Pd / C (0.5 g) and NaBH4 (1.06 g, 27.88 mmol) were added to N-(3-chloro-4-fluorophenyl)-4-5-hydroxy-5-(1-methyl-3-nitro-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide under a nitrogen atmosphere.A stirred solution of 2 g (3.98 mmol) of cyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide in MeOH (20 mL) was prepared according to the instructions on page 64 of page 61 / 163 of CN 121248511 A. The reaction mixture was stirred at 0 °C for 30 min. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was filtered through a diatomaceous earth pad and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 4-5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (1.5 g, 80%) as a creamy white solid. TLC: 10% MeOH / DCM (Rf: 0.1). ¹H NMR (400MHz, DMSO-d⁶): δ 10.25 (s, ¹H), 7.95 (d, J = 4.4Hz, ¹H), 7.76 (s, ¹H), 7.58–7.54 (m, ¹H), 7.41 (t, J = 9.2Hz, ¹H), 6.62–5.57 (br s, 2H), 5.39 (s, ¹H), 5.17 (s, ¹H), 3.69 (s, 6H), 3.32–3.31 (m, ¹H, combined), 2.50–2.32 (m, 2H, combined), 2.29–2.11 (m, 4H), 1.85–1.83 (m, 4H)ppm; MS calculation: C23H26ClFN6O2; 472.2; Actual measurement: 471.2 [M-1]-.

[0455] Example 52

[0456]

[0457] 4-(5-(3-amino-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. Selectfluor (0.149 g, 0.42 mmol) and DIPEA (0.147 mL, 0.84 mmol) were added to a stirred solution of 4-(5-(3-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (0.2 g, 0.42 mmol) in ACN (5 mL). The reaction mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 4-(5-(3-amino-4-fluoro-1-methyl-1H-)Pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (0.02 g, 10%) is an off-white solid. TLC: 10% MeOH / DCM (Rf: 0.3). ¹H NMR (400MHz, DMSO-d⁶): δ 10.19 (s, ¹H), 7.95 (dd, J = 6.8, 2.4Hz, ¹H), 7.63 (s, ¹H), 7.57–7.53 (m, ¹H), 7.39 (t, J = 9.6Hz, ¹H), 5.21 (s, ¹H), 4.47 (s, 2H), 3.66 (s, 3H), 3.60 (s, 3H), 3.30–3.14 (m, ¹H), 2.50–2.40 (m, 2H, combined), 2.23–2.16 (m, 2H), 2.07–2.04 (m, 2H), 1.96–1.83 (m ,4H). MS calculation: C23H25ClF2N6O2:490.2; Actual measurement: 473.1[M-H2O+1] +.

[0458] Intermediate 21

[0459]

[0460] Methyl 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)propionate. n-BuLi (1.19 g, 18.6 mmol) was added to a stirred solution of propionate (1.56 g, 18.6 mmol) in dry THF (40 mL) at -78 °C under an inert atmosphere. The reaction mixture was stirred for 30 minutes. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (1 g, 2.66 mmol) in THF was added at -78 °C. The resulting reaction mixture was stirred at -78 °C for 2 h. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give methyl 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazolium-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)propionate, a white solid, as a single diastereomer. TLC: 5% MeOH / DCM (Rf: 0.3); 1H NMR (400MHz, DMSO‑d6): δ10.23 (s, 1H), 7.95 (d, J=6.4Hz, 1H),7.74–7.68 (m, 1H), 7.59–7.55 (m, 1H), 7.40 (t, J = 8.8 Hz, 1H), 5.79 (s, 1H), 3.69 (s, 3H), 3.63 (s, 3H), 3.28–3.23 (m, 1H), 2.58–2.54 (m, 2H), 2.09–2.06 (m, 4H), 1.80–1.76 (m, 4H) ppm. MS calculation: C23H23ClFN3O4: 459.1; measured: 460.2 [M+1]+.

[0461] Example 53

[0462]

[0463] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. TEA (2 g, 19.82 mmol) and 3-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)propionate (1.3 g, 2.83 mmol) were added to a stirred solution of methylhydrazine sulfate (2.85 g, 19.82 mmol) in EtOH (20 mL). The reaction mixture was stirred at 50 °C for 24 hours. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.65 g, 49%), a white solid. TLC: 8% MeOH / DCM (Rf: 0.2); 1H NMR (400MHz, DMSO-d6): δ 10.18 (s, 1H), 9.27 (s, 1H), 7.95 (d, J = 4.4Hz, 1H), 7.64 (s, 1H), 7.61–7.55 (m, 1H), 7.39 (t, J = 8.8Hz, 1H), 5.28 (s, 1H), 5.13 (s, 1H), 3.66 (s, 6H), 3.38–3.18 (m, 1H, combined), 2.60–2.38 (m, 2H, combined), 2.20–2.01 (m, 4H), 1.91–1.75 (m, 4H) ppm. MS calculation: C23H25ClFN5O3: 473.2; Actual measurement: 473.9 [M+1]+.

[0464] Example 54 Specification 63 / 163 pages 66 CN 121248511 A

[0465]

[0466] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-isopropoxy-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. The title compound was synthesized by alkylation of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide using method A. 1H NMR (400MHz, DMSO‑d6): δ10.21(s,1H) ,7.99‑7.94(m,1H) , 7.64(s ,1H) ,7.60‑7.54(m ,1H) ,7.40(t,J=9.2Hz,1H) ,5.47(s ,1H) ,5.20(s ,1H) ,4.61‑ 4.54(m,1H) ,3.71(s,3H) ,3.67(s,3H) ,3.29‑3.18(m,1H) ,2.48‑2.39(m,2H) ,2.20‑2.04(m, 4H) ,1.90-1.78(m,4H) ,1.21 (d, J = 6.4 Hz, 6H) ppm; TLC: 10% MeOH / DCM (Rf: 0.3); MS calculation: C26H31ClFN5O3: 515.2; Actual measurement: 516.1 [M+1]+.

[0467] Example 55

[0468]

[0469] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. MeMgBr (3M in DEE, 0.59 mL, 1.78 mmol) was slowly added to a stirred solution of 2-((5-(5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)ethyl acetate (0.5 g, 0.89 mmol) in dry THF (5 mL) under an inert atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography followed by preparative HPLC to N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxy-2-methylpropoxy)-1-Methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.501 g, 61%) is a creamy white solid. TLC: 5% MeOH / DCM (Rf: 0.4); 1H NMR (400MHz, DMSO‑d6): δ10.22 (s, 1H), 7.96 (dd, J=6.8Hz, 2.4Hz, 1H), 7.65 (s, 1H), 7.59‑7.52 (m, 1H), 7 .40(t,J=9.6Hz, 1H) ,5.52(s,1H) ,5.23(s,1H) ,4.53(s,1H) ,3.75‑3.70(m,5H) ,3.67(s,3H) ,3.26‑3.20(m, 1H) ,2.50‑2.44(m,2H) ,2.20-2.06(m,4H) ,1.90-1.80(m,4H) ,1.13(s,6H)ppm. MS calculation: C27H33ClFN5O4:545.2; Actual measurement: 546.3[M+1]+. Specification 64 / 163 pages 67 CN 121248511 A

[0470] Intermediate 22

[0471]

[0472] 4-(5-(3-bromo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. n-BuLi (2M in THF, 7.8 mL, 15.96 mmol) was added dropwise to a stirred solution of 3,5-dibromo-1-methyl-1H-pyrazole (3.8 g, 15.96 mmol) in dry THF (50 mL) at -78 °C under an inert atmosphere, and the reaction mixture was stirred at the same temperature for 35 min. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (1 g, 2.65 mmol) in THF was slowly added to the mixture at -78 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography to give 4-(5-(3-bromo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (0.46 g, 32.39%). TLC: 5% MeOH / DCM (Rf: 0.3) 1H NMR(400MHz, DMSO-d6): δ 10.21(s, 1H), 7.95(dd, J=6.8, 2.4Hz, 1H), 7.65(s, 1H), 7.58–7.55 (m, 1H), 7.40(t, J=9.2Hz, 1H), 6.23(s, 1H), 5.37(s, 1H), 3.87(s, 3H), 3.67(s, 3H), 3.29–3.23(m, 1H), 2.50–2.46(m, 2H, combined), 2.22–2.07(m, 4H), 1.87–1.83(m, 4H)ppm; MS calculation: C23H24BrClFN5O2: 535.1; Actual measurement: 536.1 [M+1]+.

[0473] Example 56

[0474]

[0475] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(prop-1-yn-1-yl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Tributyl(1-propynyl)tin (153.7 mg, 0.46 mmol) was added to a stirred solution of 4-(5-(3-bromo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (50 mg, 0.09 mmol) in 1,4-dioxane (3 mL). The mixture was purified with argon for 15 min. Pd(PPh3)4 (10.39 mg, 0.009 mmol) was then added, and the mixture was further purified with argon for 10 min. The reaction mixture was stirred in a microwave oven at 140 °C for 45 min. The reaction progress was monitored by TLC and LCMC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate (see page 68 of the manual, CN 121248511 A) and concentrated under reduced pressure. The crude compound was purified by column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(prop-1-yn-1-yl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (6 mg, 12%), a creamy white solid. TLC: 5% MeOH / DCM (Rf: 0.4); 1H NMR (400MHz, CD3OD): δ7.92-7.87(m,1H),7.66(s,1H),7.55-7.48(m,1H),7.24(t,J=8.8Hz,1H),6.21(s,1H) ,3.94(s,3H) ,3.77(s,3H),3.38-3.26 (m, 1H, combined), 2.62-2.52 (m, 2H), 2.43-2.34 (m, 2H), 2.32-2.22 (m, 2H), 1.99 (s, 3H), 1.97-1.82 (m, 4H) ppm (amide and OH protons not observed); MS calculation: C26H27ClFN5O2: 495.2; Actual measurement: 496.0.

[0476] Example 57

[0477]

[0478] N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Zn(CN)₂ (49.4 mg, 0.42 mmol) and zinc dust (4.5 mg, 0.07 mmol) were added to a stirred solution of 4-(5-(3-bromo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (150 mg, 0.28 mmol) in DMA (3 mL). The mixture was purified with argon for 10 min. Pd₂(dba)₃ (12.8 mg, 0.014 mmol) and dppf (15.5 mg, 0.028 mmol) were added to this solution, and purification with argon was continued for another 10 min. The resulting mixture was stirred at 130 °C for 12 h. The reaction progress was monitored by TLC. After completion, the mixture was filtered through a diatomaceous earth filter and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazol-5-yl)-5-hydroxy-octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide, a white solid. TLC: 5% MeOH / DCM (Rf: 0.4); ¹H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 7.98–7.91 (m, 1H), 7.64 (s, 1H), 7.59–7.52 (m, 1H), 7.38 (t, J = 8.8 Hz, 1H), 6.85 (s, 1H), 5.50 (s, 1H), 3.99 (s, 3H). 3.66 (s, 3H), 3.42–3.16 (m, 1H, combined), 2.59–2.34 (m, 2H, combined), 2.28–2.02 (m, 4H)1.95-1.76 (m, 4H) ppm; MS calculation: C24H24ClFN6O2: 482.2; Actual measurement: 483.1 [M+1]+.

[0479] Example 58

[0480] Specification 66 / 163 pages 69 CN 121248511 A

[0481] 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. MeMgI (3M in DEE, 0.13 mL, 0.419 mmol) was slowly added at 0 °C under an inert atmosphere to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (50 mg, 0.103 mmol) in dry THF (5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to obtain 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (40 mg, 77.2%), which was a creamy white solid. TLC: 5% MeOH / DCM (Rf: 0.4); ¹H NMR (400MHz, DMSO-d6): δ 10.20 (s, ¹H), 7.98–7.92 (m, ¹H), 7.65 (s, ¹H), 7.60–7.54 (m, ¹H), 7.40 (t, J = 8.0Hz, ¹H), 6.53 (s, ¹H), 5.39 (s, ¹H), 4.00 (s, ³H), 3.68 (s, ³H), 3.40–3.20 (m, ¹H, combined), 2.55–2.20 (m, 2H, combined), 2.42 (s, ³H), 2.28–2.20 (m, 2H) ,2.15-2.05(m,2H) ,1.94-1.85(m,4H)ppm. MS calculation: C25H27ClFN5O3:499.2; Actual measurement: 482.1[M-H2O+1]+.

[0482] Example 59

[0483]

[0484] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxypropyl-2-yl)-1-methyl-1H-pyrazol-5-yl)Octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. MeMgI (3M in DEE, 0.66 mL, 2 mmol) was slowly added to a stirred solution of 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (100 mg, 0.2 mmol) in dry THF (5 mL) under an inert atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to obtain N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(2-hydroxypropyl-2-yl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (40 mg, 39%), which was a creamy white solid. TLC: 5% MeOH / DCM (Rf: 0.2); 1H NMR (400MHz, DMSO‑d6): δ10.20(s,1H),7.96(d,J=5,2Hz,1H),7.65(s,1H),7.60‑7.54(m,1H),7.40(t,J=9.2Hz,1H) ,6.01(s,1H) ,5.18(s,1H) ,4.67(s,1H) ,3.83(s,3H) ,3.68(s,3H) ,3.28‑3.20 (m,1H) ,2.55‑2.40(m,2H,combined) ,2.22‑2.16(m,2H) ,2.10-2.08(m,2H) ,1.90-1.84(m,4H) ,1.36(s,6H)ppm;MS calculation: C26H31ClFN5O3:515.2; Actual measurement: 516.2[M+1]+.

[0485] Example 60 Specification 67 / 163 Page 70 CN 121248511 A

[0486]

[0487] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. NaBH4 (3 mg, 0.08 mmol) was added at 0 °C to 4-(5-(3-acetyl-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (20 mg).0.04 mmol) was added to a stirred solution of MeOH (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography followed by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (5 mg, 25%). TLC: 10% MeOH / DCM (Rf: 0.4); 1H NMR (400MHz, DMSO‑d6): δ10.21(s,1H),7.96 (d,J=4.0Hz,1H),7.65(s,1H),7.60‑7.54(m,1H),7 .40(t,J=9.2Hz,1H) ,6.00(s ,1H) , 5.19(s ,1H) ,4.84(d ,J=4.8Hz ,1H) ,4.57(t ,J=5.6Hz ,1H) ,3.83(s ,3H) ,3.67(s ,3H) , 3.30‑3.20(m ,1H , combined), 2.55-2.40 (m, 2H, combined), 2.20-2.05 (m, 4H), 1.88-1.82 (m, 4H), 1.29 (d, J = 6.4 Hz, 3H) ppm; MS calculation: C25H29ClFN5O3: 501.2; Actual measurement: 502.1 [M+1]+.

[0488] Example 61

[0489]

[0490] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-hydroxy-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Selectfluor (2.99 g, 8.45 mmol) was added to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (2 g, 4.22 mmol) in DMF (40 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and extracted with 10% MeOH / DCM. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude compound was then subjected to...The product was purified by column chromatography to obtain N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-hydroxy-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.55 g, 38%), which was a white solid. TLC: 10% MeOH / DCM (Rf: 0.2); ¹H NMR (400MHz, DMSO-d⁶): δ 10.21 (s, ¹H), 10.00–9.80 (m, ¹H), 7.96 (d, J = 5.2Hz, ¹H), 7.64 (s, ¹H), 7.58–7.54 (m, ¹H), 7.40 (t, J = 8.0Hz, ¹H), 5.30 (s, ¹H), 3.67 (s, 3H), 3.65 (s, 3H), 3.25–3.20 (m, ¹H, combined), 2.60–2.45 (m, 2H, combined) ,2.25-2.18 (m, 2H), 2.09-2.06 (m, 2H), 1.96-1.87 (m, 4H) ppm; MS calculation: C23H24ClF2N5O3: 491.2; Actual: 492.1 [M+1]+.

[0491] Example 62

[0492]

[0493] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-1-methyl-3-(3,3,3-trifluoro-2-hydroxypropoxy)-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. The title compound was synthesized by the general procedure (method B) for alkylation described above. TLC: 10% MeOH / DCM (Rf: 0.3); 1H NMR (400MHz, DMSO‑d6): δ10.20 (s, 1H), 7.96 (d, J = 6.0Hz, 1H), 7.64 (s, 1H), 7.60‑7.54 (m, 1H), 7.40(t,J=9.2Hz,1H) ,6.62(d ,J=6.8Hz,1H) ,5.39(s,1H) ,4.45‑4.35(m,1H) ,4.30‑4.24 (m,1H) ,4.18‑4.12(m,1H) ,3.73(s,3H) ,3.67(s,3H) ,3.26‑3.18(m,1H) 2.60–2.50 (m, 2H, combined). 2.25–2.20 (m, 2H), 2.10–2.06 (m, 2H), 1.94–1.88 (m, 4H) ppm; MS calculation isC26H27ClF5N5O4: 603.2; Actual: 586.2 [M-H2O+1] +.

[0494] Intermediate 23

[0495]

[0496] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. LDA (5.33 mL, 10.66 mmol) was added dropwise to a stirred solution of 4-fluoro-3-iodo-1-methyl-1H-pyrazol (2.42 g, 10.66 mmol) in dry THF (30 mL) at -78 °C, and the reaction mixture was stirred at the same temperature for 2 hours. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (0.4 g, 1.06 mmol) in THF was added at -78 °C. The reaction mixture was stirred at the same temperature and then at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.250 g, 40.62%), a white solid, as a single diastereomer. TLC: 5% MeOH / DCM (Rf: 0.3). 1H NMR (400MHz, datasheet 69 / 163, page 72, CN 121248511 A DMSO-d6): δ 10.20 (s, 1H), 7.98–7.94 (m, 1H), 7.65 (s, 1H), 7.60–7.54 (m, 1H), 7.40 (t, J = 9.2Hz, 1H), 5.44 (s, 1H), 3.89 (s, 3H), 3.67 (s, 3H), 3.28–3.18 (m, 1H), 2.55–2.40 (m, 2H, combined), 2.24–2.18 (m, 2H), 2.10–2.06 (m, 2H), 1.98–1 .90 (m, 4H) ppm. MS calculation: C23H23ClF2IN5O2: 601.1; observed: 602.1 [M+1]+.

[0497] Example 63

[0498]

[0499] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-((2-hydroxy-2-methylpropyl)amino)-1-methyl-1H-pyridineN-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. K₂CO₃ (99 mg, 0.415 mmol) and L-proline (7.6 mg, 0.066 mmol) were added to a mixture of N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (100 mg, 0.166 mmol) and 1-amino-2-methylprop-2-ol (29.6 mg, 0.33 mmol) in DMSO (3 mL). The solution was purified with argon for 10 minutes. CuI (6.3 mg, 0.033 mmol) was added to the solution, and purification with argon was continued for another 10 minutes. The resulting reaction mixture was stirred at 90 °C for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with 10% MeOH / DCM. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-((2-hydroxy-2-methylpropyl)amino)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (20 mg, 21%). TLC: 10% MeOH / DCM (Rf: 0.2). ¹H NMR (400MHz, DMSO-d⁶) δ 10.21 (s, ¹H), 7.95 (d, J = 6.8Hz, ¹H), 7.64 (s, ¹H), 7.58–7.54 (m, ¹H), 7.40 (t, J = 9.2Hz, ¹H), 5.25 (s, ¹H), 4.53 (t, J = 6.4Hz, ¹H), 4.45 (s, ¹H), 3.67 (s, 3H), 3.64 (s, 3H), 3.26–3.22 (m, ¹H), 2.94 (d, J = 6.0Hz, 2H), 2.55–2.40 (m, 2H, combined), 2.25–2.20 (m, 2H) ,2.12-2.06(m,2H), 1.98-1.85(m,4H), 1.10(s,6H)ppm. MS calculation: C27H33ClF2N6O3:562.2; Actual measurement: 563.2[M+1]+.

[0500] Example 64

[0501]

[0502] N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Zn(CN)2(O0.073 g (0.623 mmol) and zinc dust (instructions page 70 / 163, CN 121248511 A) were added to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-iodo-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.25 g, 0.415 mmol) in DMA (5 mL), and the solution was purified with argon for 10 minutes. Pd2(dba)3 (0.038 g, 0.0415 mmol) and dppf (0.023 g, 0.0415 mmol) were added to this solution, and the solution was further purified with argon for 10 minutes. The resulting reaction mixture was stirred at 120 °C for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.160 g, 77%), a creamy white solid. TLC: 5% MeOH / DCM (Rf: 0.4). MS calculation: C24H23ClF2N6O2: 500.2; actual: 501.1 [M+1]+.

[0503] Example 65

[0504]

[0505] 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. MeMgI (3M in diethoxyethane, 0.5 mL, 1.5 mmol) was slowly added at 0°C under an inert atmosphere to a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-cyano-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (0.15 g, 0.3 mmol) in dry THF (5 mL). The reaction mixture was stirred at 50°C for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (0.105 g).(67%), it is an off-white solid. TLC: 5% MeOH / DCM (Rf: 0.2). ¹H NMR (400MHz, DMSO-d⁶): δ 10.21 (s, ¹H), 7.96 (d, J = 6.4Hz, ¹H), 7.65 (s, ¹H), 7.60–7.54 (m, ¹H), 7.40 (t, J = 6.4Hz, ¹H), 5.49 (s, ¹H), 3.99 (s, 3H), 3.67 (s, 3H), 3.32–3.20 (m, ¹H), 2.60–2.50 (m, 2H, combined), 2.41 (s, 3H), 2.35–2.20 (m, 2H), 2.10–2.05 (m, 2H), 2.00–1.94 (m,4H)ppm; LCMS calculated as: C25H26ClF2N5O3: 517.2; Actual measurement: 518.1 [M+1]+.

[0506] Example 66

[0507]

[0508] N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-(2-hydroxypropyl-2-yl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. MeMgI (3M in diethoxyethane, 0.32 mL, 0.96 mmol) was slowly added to a stirred solution of 4-(5-(3-acetyl-4-fluoro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (0.1 g, 0.193 mmol) in dry THF (3 mL) at 0 °C under an inert atmosphere. The reaction mixture was stirred at 50 °C for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with saturated ammonium chloride (water) solution and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-(4-fluoro-3-(2-hydroxypropyl-2-yl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (12 mg, 12%), which was a creamy white solid. TLC: 5% MeOH / DCM (Rf: 0.2); 1H NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 7.96 (d, J = 6.4 Hz, 1H), 7.92–7.62 (m, 1H), 7.60–7.54 (m, 1H), 7.41 (t, J = 9.2 Hz, 1H).,5.31(s,1H), 4.81(br.s,1H), 3.81(s,3H), 3.70(s,3H), 3.30-3.20(m,1H, combined), 2.60-2.45(m,2H, combined), 2.30-2.10(m,4H), 1.96-1.90(m,4H), 1.41(s,6H)ppm; MS calculation: C26H30ClF2N5O3:533.2; Actual measurement: 534.1[M+1]+.

[0509] Intermediate 24

[0510]

[0511] Ethyl 2-((5-(-5-(5-((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)propionate. The title compound was synthesized according to the general procedure for alkylation (Method B). TLC: 5% MeOH / DCM (Rf: 0.5); MS calculation: C28H33ClFN5O5: 573.2; actual: 572.4 [M-1]-.

[0512] Example 67

[0513]

[0514] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(((1-hydroxypropyl-2-yl)oxy)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. NaBH4 (0.133 g, 3.49 mmol) was added at 0 °C to a stirred solution of ethyl 2-((5-(-5-(5-(((3-chloro-4-fluorophenyl)carbamoyl)-1-methyl-1H-imidazol-4-yl)-2-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazol-3-yl)oxy)propionate (0.2 g, 0.349 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After completion, the reaction was concentrated under reduced pressure. The residue was diluted with saturated NH4Cl and extracted with ethyl acetate. The organic layer was collected; washed with brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography followed by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(3-(((1-hydroxypropyl-2-yl)oxy)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (60 mg, 32.4%). Racemic compounds were submitted for chiral preparative HPLC purification to obtain two diastereomers: Example 68 (diastereomer 1) and Example 69 (diastereomer 2) (Table 5)

[0515] Table 5. Examples 68 and 69

[0516]

[0517] Intermediate 25

[0518]

[0519] 1-(5-bromo-1-methyl-1H-pyrazole-4-yl)-N,N-dimethylmethylamine. 5-bromo-1-methyl-1H-pyrazole-4-carboxaldehyde (2.0 g, 10.59 mmol) was added at room temperature to a stirred solution of dimethylamine hydrochloride (4.32 g, 52.96 mmol, 5.0 equivalent), triethylamine (52.95 mmol, 7.38 mL, 5.0 equivalent) and acetic acid (1.91 g, 31.78 mmol, 1.83 mL, 3.0 equivalent) in 30 mL of dry DCM. The resulting mixture was stirred for 20 minutes, followed by a single addition of sodium triacetoxyborohydride (13.47 g, 63.55 mmol, 6.0 equivalents). The resulting suspension was stirred overnight. After the reaction was complete, the mixture was poured into a stirred aqueous solution of NaHCO3. The organic phase was separated, washed with brine, and concentrated under reduced pressure to give 1-(5-bromo-1-methyl-1H-pyrazol-4-yl)-N,N-dimethylmethylamine (2.2 g, 90.0% purity, 9.08 mmol, 86% yield). MS calculation: C7H12BrN3: 217.0; Actual determination: 218.1 [M+1]+.

[0520] Example 70

[0521]

[0522] N-(3-chloro-4-fluorophenyl)-4-(5-(4-((dimethylamino)methyl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Butyllithium (2.5 M in n-hexane, 1.7 mmol, 0.68 mL, 8.0 equivalents) was added dropwise to a solution of 1-(5-bromo-1-methyl-1H-pyrazol-4-yl)-N,N-dimethylmethylamine (372.65 mg, 1.71 mmol, 8.0 equivalents) in anhydrous THF (10 mL) at -78°C. The resulting mixture was stirred for 30 minutes, then heated to -60°C over 30 minutes, and subsequently cooled to -78°C. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (80 mg, 213.58 μmol) in THF (2 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at -78 °C for 1 hour and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and then extracted with EtOAc (3 x 10 mL). The combined organic solutions were dried over Na2SO4 and evaporated under vacuum to give 0.12 g of crude product. N-(3-chloro-4-fluorophenyl)-4-(5-(4-)-1H-imidazolium-5-carboxamide was purified by preparative HPLC.((dimethylamino)methyl)-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (26.0 mg, 50.48 μmol, 23.6% yield), as a single diastereomer. MS calculation: C26H32ClFN6O2: 514.1; Measured: 515.2 [M+1]+; 1H NMR (400MHz, chloroform-d): δ 7.78 (dd, J = 6.5, 2.6Hz, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 7.42–7.35 (m, 1H), 7.22 (s, 1H), 7.16 (t, J = 8.7Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.37 (s, 2H), 3.23 (dq, J = 12.1, 6.1Hz, 1H), 2.87 (s, 2H), 2.50–2.33 (m, 4H) ,2.32-2.25(m,2H) ,2.21(s,6H) ,2.12(s,1H) ,2.09(s,1H) ,2.03(d ,J= 4.6Hz,1H)ppm.

[0523] Example 71

[0524]

[0525] N-(3-chloro-4-fluorophenyl)-4-(5-(1,3-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. To a solution of 1,3-dimethyl-1H-pyrazole (211.0 mg, 2.2 mmol) in anhydrous THF (20 mL), n-butyllithium (2.5 M in n-hexane, 2.2 mmol, 0.88 mL, 11.0 equivalent) was added dropwise at -78 °C. The resulting mixture was stirred for 10 min and then warmed to -5 °C over 30 min. The reaction mixture was cooled to -78 °C and a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (75.0 mg, 199.56 μmol) in THF (2 mL) was added dropwise. The mixture was stirred at -78 °C for 30 min and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and then extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried over Na2SO4 and evaporated under vacuum to give 0.1 g of crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-(1,3-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide.As a single diastereomer (6.7 mg, 14.2 μmol, 7.1% yield). MS calculation: C24H27ClFN5O2: 471.2; Measured: 454.2 [M-H2O+1]+; 1H NMR (400MHz, chloroform-d): δ 7.79 (d, J=6.8Hz, 2H), 7.55 (s, 1H), 7.37 (s, 1H), 7.15 (t, J=8.6Hz, 1H), 5.87 (s, 1H), 3.96 (s, 3H), 3.85 (s, 3H), 3.29 (s, 1H), 3.00 (s, 2H), 2.74 (s, 2H), 2.31 (dd, J=21.5, 13.4Hz, 5H), 2.21 (d, J=2.1Hz, 3H) ,2.13 (d, J = 13.3 Hz, 2H) ppm.

[0526] Example 72

[0527]

[0528] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. n-Butyllithium (2.5 M in n-hexane, 2.05 mmol, 0.82 mL, 11.0 equivalent) was added dropwise to a solution of diisopropylamine (207.41 mg, 2.05 mmol, 290.0 μl, 11.0 equivalent) in anhydrous THF (20 mL) at -78 °C. The resulting mixture was stirred for 10 minutes and then warmed to -10 °C over 10 minutes. The mixture was cooled to -78°C and a solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazole (307.67 mg, 2.05 mmol) in THF (1 mL) was added. The reaction mixture was stirred at -70°C for 1 hour, followed by dropwise addition of a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (70.0 mg, 186.26 μmol) in THF (2 mL). The mixture was stirred at -70°C for 30 minutes and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried over Na₂SO₄ and then evaporated under vacuum to obtain 0.15 g of crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-formylAmine, as a single diastereomer (20.1 mg, 38.22 μmol, 21% yield). MS calculation: C24H24ClF4N5O2: 525.2; Measured: 526.2 [M+1]+; 1H NMR (400MHz, chloroform-d): δ 7.77 (dd, J = 6.5, 2.5Hz, 1H), 7.58 (s, 1H), 7.40–7.33 (m, 1H), 7.31 (s, 1H), 7.15 (td, J = 8.7, 1.7Hz, 1H), 6.34 (s, 1H), 4.10 (s, 3H), 3.81 (d, J = 1.7Hz, 3H), 3.30 (tt, J = 11.8, 6.6Hz, 1H), 2.84–2.67 (m, 3H) ,2.39-2.14 (m, 8H) ppm.

[0529] Example 73 Specification 75 / 163 pages 78 CN 121248511 A

[0530]

[0531] 4-(5-(3-chloro-1-methyl-1H-pyrazole-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide. To a solution of 3-chloro-1-methyl-1H-pyrazole (124.04 mg, 1.06 mmol) in tetrahydrofuran (10 mL), n-butyllithium (1.06 mmol, 430.0 μl, 2.5 M in hexane, 4.0 equivalent) was added dropwise at -78 °C, and the resulting mixture was stirred for 10 minutes. The reaction temperature was raised to -30°C and stirred for 30 minutes. The reaction mixture was cooled to -78°C and a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (100 mg, 266.06 μmol) in tetrahydrofuran (2 mL) was added dropwise, and stirring was continued for 15 minutes. The resulting mixture was warmed to room temperature and quenched with saturated ammonium chloride. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC to give 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (2.2 mg, 95.0% purity, 4.24 μmol, 1.6% yield). MS calculations: C23H24Cl2FN5O2: 491.1; Observed: 493.0 [M+2]+; 1H NMR (400 MHz, methanol-d4): δ 7.89 (dd, J = 6.7, 2.6 Hz, 1H).,7.66(s,1H) ,7.55-7.47 (m,1H) ,7.25(t,J=9.0Hz,1H) ,6.15(s,1H) ,3.94(s,3H) ,3.78(s,3H) ,3.68-3.42(m,1H) ,2.59(s,2H) ,2.37(dd,J=13.4,7.2Hz,2H) ,2.32-2.21(m,2H) ,2.04-1.82(m,4H)ppm.

[0532] Example 74

[0533]

[0534] 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. n-Butyllithium (109.0 mg, 1.7 mmol, 680.0 μl, 8.0 equivalent) was added dropwise to a solution of 3-tert-butyl-1-methyl-1H-pyrazol (234.46 mg, 1.7 mmol) in tetrahydrofuran (10 mL) at -78 °C, and the mixture was stirred for 10 minutes. The reaction temperature was then increased to -60 °C and stirred for 1 hour. The mixture was then cooled to -78°C and 4-[-5-oxo-octahydrocyclopentadien-2-yl]-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazolium-5-carboxamide (79.69 mg, 212.05 μmol) was added dropwise to a solution of tetrahydrofuran (2 mL). The reaction mixture was stirred at -78°C for 15 min. The resulting mixture was warmed to room temperature and quenched with saturated ammonium chloride. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC to give 4-(5-(3-chloro-1-methyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (2.8 mg, 97.8% purity, 5.33 μmol, 2.5% yield). MS calculation: C27H33ClFN5O2: 513.2; Actual measurement: 512.0 [M-H]-; 1H. Specification 76 / 163, page 79. CN 121248511. A NMR (400MHz, methanol-d4): δ 7.88 (dd, J = 6.5, 2.7Hz, 1H), 7.65 (s, 1H), 7.51 (d, J = 2.4Hz, 2H), 7.25 (t, J = 8.9Hz, 1H), 6.14 (d, J = 2.4Hz, 1H), 4.09 (s, 2H), 3.77 (s, 3H), 2.67 (s, 1H), 2.58 (s, 2H), 2.22 (d...,J=8.2Hz,2H) ,2.05(s ,1H) ,1 .86(t,J=6.6Hz ,2H) ,1 .81-1 .71(m ,2H) ,1.56-1.46(m ,2H) ,1.29(d,J=2.1Hz,9H)ppm.

[0535] Intermediate 26

[0536]

[0537] A mixture of 3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole.1,4-dimethyl-1H-pyrazole-3-amine (2.1g ,18.9mmol) and hexane-2,5-dione (2.22mL,18.9mmol) and catalytic TsOH in toluene (100mL) was refluxed overnight using a Dean-Stark condenser. The reaction mixture was then cooled to room temperature and carefully decanted from the insoluble material. The resulting solution was evaporated under reduced pressure and further dried under vacuum for several hours to provide 3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole.

[0538] Intermediate 27

[0539]

[0540] N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazolium-5-carboxamide. n-BuLi (0.85 mL, 2.5 M, 2.1 mmol) was added to a solution of 3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole (400 mg, 2.1 mmol) in THF (8 mL) at -78 °C under argon atmosphere. The mixture was stirred at -50 °C for 2.5 h. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (80 mg, 0.2 mmol) in THF (1.5 mL) was added to the resulting mixture at -78 °C. The resulting mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude compound (420 mg), which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (11 mg, 9% yield).

[0541] Example 75

[0542] Specification 77 / 163 pages 80 CN 121248511 A

[0543] 4-(5-(3-amino-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. Hydroxylamine hydrochloride (270 mg, 3.9 mmol) and KOH solution (4.7 mL, 4.5% in EtOH:H2O 1:1, 3.8 mmol) were added to a solution of N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrole-1-yl)-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (11 mg, 0.02 mmol) in EtOH (1 mL). The resulting mixture was refluxed for 2 days. Subsequently, additional hydroxylamine hydrochloride (270 mg, 3.9 mmol) and triethylamine (0.528 mL, 3.85 mmol) were added, and the resulting mixture was refluxed for 2 days. The previous step was repeated. EtOH was evaporated from the cooled reaction mixture, the product was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give a crude compound, which was purified by preparative HPLC to give 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide (2.7 mg, 28% yield). MS calculation: C24H28ClFN6O2: 486.2; Measured: 485.2 [M-1]-; 1H NMR (600MHz, acetonitrile-d3): δ 8.30 (s, 1H), 7.88 (dd, J = 6.8, 2.6Hz, 1H), 7.53 (ddd, J = 9.0, 4.2, 2.6Hz, 1H), 7.46 (s, 1H), 7.26 (t, J = 9.0Hz, 1H), 3.74 (d, J = 14.5Hz, 6H), 3.54 (s, 2H), 3.29 (dt, J = 11.6, 5.5Hz, 1H), 3.04 (s, 1H) ,2.70(s, 2H),2.28(dd, J = 13.6, 8.3Hz, 2H),2.13(s, 3H),2.07(dt, J = 4.9, 2.5Hz, 2H),1.85(qt, J = 6.1, 3.5Hz, 2H)ppm.

[0544] Intermediate 28

[0545]

[0546] 3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1-ethyl-1H-pyrazole. As described, it is used for 3-(2,5-dimethyl-Synthesis of the title compound using a programmed procedure for N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole)-1-methyl-1H-imidazolium-5-carboxamide. The title compound is synthesized according to the described procedure for N-(3-chloro-4-fluorophenyl)-4-(5-(3-(2,5-dimethyl-1H-pyrrolo-1-yl)-1,4-dimethyl-1H-pyrazole-5-yl)-5-hydroxy-octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazolium-5-carboxamide. (25 mg, 95% purity, 22% yield). MS calculation: C30H34ClFN6O2: 564.2; Measured: 563.1 [M-H]-; 1H NMR (600 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.94 (dd, J = 6.8, 2.6 Hz, 1H), 7.64 (s, 1H), 7.55 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.38 (t, J = 9.1 Hz, 1H), 6.08 (s, 1H), 5.70 (s, 2H), 5.43 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.66 (s, 3H) ,3.23(dt,J=12.2,6.1Hz,1H) ,2.51(dd ,2H) ,2.23(dd ,J=13.1,7.8Hz,2H) ,2.08(dt,J=7.7,6.8Hz,2H) ,2.01(s,6H) ,1.93-1.80(m,4H) ,1.34(t,J=7.1Hz,3H)ppm.

[0550] Example 76 Specification 78 / 163 pages 81 CN 121248511 A

[0551]

[0552] 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N- (3-Chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. The title compound was synthesized according to the procedure described for 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. MS calculations: C24H28ClFN6O2: 486.2; Found: 485.0 [M-1]-; 1H NMR (400MHz, chloroform-d): δ 7.77 (dd).,J=6.5,2.6Hz,1H),7.52(s,1H),7.43-7.30(m,2H),7.15 (t,J=8.7Hz,1H),5.42(s,1H),4.22(q,J=7.1Hz,2H),3.83(s,3H),3.50(s,1H),3.26(dd,J=11.7,5.2Hz,1H),2.73(s,3H),2.35-2.04(m,8H),1.39(t,J=7.1Hz,3H)ppm.

[0553] Example 77

[0554]

[0555] 4-(5-(3-amino-1-isopropyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. The title compound is synthesized according to the provided method for 4-(5-(3-amino-1,4-dimethyl-1H-pyrazol-5-yl)-5-hydroxyoctahydrocyclopentadien-2-yl)-N-(3-chloro-4-fluorophenyl)-1-methyl-1H-imidazol-5-carboxamide. MS calculation: C25H30ClFN6O2: 500.2; Measured: 499.2 [M-1]-; 1H NMR (400MHz, chloroform-d): δ 7.78 (d, J = 7.4Hz, 1H), 7.49 (s, 2H), 7.35 (d, J = 8.0Hz, 1H), 7.16 (t, J = 8.7Hz, 1H), 5.42 (s, 1H), 5.03–4.89 (m, 1H), 3.85 (s, 3H), 3.28 (s, 1H), 2.74 (s, 2H), 2.38–2.22 (m, 7H), 2.10 (d, J = 12.7Hz, 4H) ,1.42 (d, J = 6.6 Hz, 6H) ppm.

[0556] Example 78

[0557]

[0558] N-(3-chloro-4-fluorophenyl)-4-(-5-hydroxy-5-(3-((S)-1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. At -78°C, n-butyllithium (2.5M in n-hexane, 4.26mmol, 1.71mL, 20.0 equivalents) was added dropwise to a solution of (R)-1-(1-methyl-1H-pyrazol-3-yl)ethanol (268.91 mg, 2.13 mmol, 10.0 equivalents) in anhydrous THF (10 mL). The resulting mixture was stirred for 30 minutes and then heated at 30°C.The mixture was heated to -30°C within minutes. A solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (80.0 mg, 212.87 μmol) in THF (2 mL) was added dropwise to the cooled (-78°C) reaction mixture. The resulting mixture was stirred at -78°C for 1 hour and then gradually warmed to room temperature. After 12 hours, the mixture was poured into saturated NH4Cl and extracted with EtOAc (3 x 10 mL). The combined organic solutions were dried over Na2SO4 and vacuum evaporated to give 0.35 g of crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(-5-hydroxy-5-(3-((S)-1-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (9.4 mg, 18.73 μmol, 8.8% yield). MS calculation: C25H29ClFN5O3: 501.2; Measured: 484.2 [M-18+1]+; 1H NMR (600MHz, acetonitrile-d3) δ 8.41 (d, J = 41.1Hz, 1H), 7.88 (dd, J = 6.8, 2.6Hz, 1H), 7.53 (ddd, J = 9.0, 4.3, 2.7Hz, 1H), 7.45 (s, 1H), 7.25 (td, J = 9.0, 1.2Hz, 1H), 6.08 (s, 1H), 4.72 (q, J = 6.5Hz, 1H), 3.90 (d, J = 1.2Hz, 3H), 3.72 (s, 3H), 3.41 (s ,1H) ,3.33(tt,J=12.0,6.1Hz, 1H) ,3.19-2.85(m,2H) ,2.61(h,J=10.1,9.3Hz,2H) ,2.32(ddd ,J=11.8,7.9,2.8Hz,2H) ,2.21(d,J=7.0Hz,1H) ,2.01(d,J=4.6Hz,2H) ,1.45-1.33(m,3H)ppm.

[0559] Intermediate 30

[0560]

[0561] 2,2,2-trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanol. A solution of TBAF (1M in THF, 9.08 μmol, 0.91 mL, 0.1 equivalent) in THF was added dropwise to a solution of 1-methyl-1H-pyrazole-3-carboxaldehyde (1.0 g, 9.08 mmol) and TMSCF3 (1.94 g, 13.62 mmol, 1.5 equivalents) in THF (20 mL) at -20 °C. The reaction mixture was stirred at 0 °C for 30 minutes.After 12 hours, an additional portion of TBAF (1M in THF, 5.0 mL) was added, the mixture was decanted into water, and extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried over Na₂SO₄ and evaporated under vacuum to give 2,2,2-trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanol, which was an oil (1.4 g, 95.0% purity, 7.38 mmol, 81% yield). The crude product was ready for use without further purification. MS calculation: C6H7F3N2O: 180.1; Actual measurement: 181.2 [M+1]+

[0562] Example 79

[0563]

[0564] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Butyllithium (2.5M in n-hexane, 3.2 mmol, 1.28 mL, 20.0 equivalents) was added dropwise at -78°C to a solution of 2,2,2-trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanol (288.36 mg, 1.6 mmol, 10.0 equivalents) in anhydrous THF (10 mL). The resulting mixture was stirred for 30 minutes and then warmed to -20°C over 30 minutes. The mixture was cooled to -78°C, and N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (60 mg, 160.09 μmol) was added dropwise to a solution in THF (page 80 / 163, CN 121248511 A, 2 mL). The reaction mixture was stirred at -78°C for 1 hour and then gradually warmed to room temperature. After 12 hours, the mixture was poured into a saturated NH4Cl solution and extracted with EtOAc (3 x 10 mL). The combined organic solutions were dried over Na2SO4 and vacuum evaporated to give 0.2 g of crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazol-5-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (6.5 mg, 11.69 μmol, 7.3% yield). MS calculation: C24H24ClF4N5O3: 541.2; Measured: 542.2 [M+1]+; 1H NMR (400MHz, acetonitrile-d3): δ 8.33 (s, 1H), 7.89 (dd, J = 6.7, 2.7Hz, 1H), 7.54 (ddd, J = 9.0, 4.2, 2.6Hz, 1H),7.49(s,1H) ,7.27(t,J=9.0Hz,1H) ,6.25(s,1H) ,5.03(q,J =7.3Hz,1H) ,4.54(s,1H) ,3.98(s,3H) ,3.74(s,3H) ,3.51(d,J=44.4Hz,1H) ,3.34(dq,J= 11.9,5.9Hz,1H) ,2.81(s,2H) ,2.34(dd ,J=13.2,7.7Hz,2H) ,2.04(dd ,J=8.8,3.6Hz,2H) ppm.

[0565] Example 80

[0566]

[0567] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(methyl-d3)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Magnesium (42.65 mg, 1.75 mmol) was stirred in a three-necked flask equipped with a thermometer and a dropping funnel in dry ether (10 mL). Trideuterium methyl iodide (231.27 mg, 1.6 mmol, 100.0 μl, 10.0 equivalent) in ether (2 mL) was added to the dropping funnel, and small crystals of iodine were added to the magnesium suspension. The magnesium suspension was briefly warmed, and then the 1,1,1-trideuterium methyl iodide solution was added dropwise to the flask. After the addition was complete, the mixture was refluxed for 30 minutes, and then cooled to -40 °C. N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide (60.0 mg, 159.65 μmol) in THF (1.5 mL) was added dropwise to the reaction mixture, which was allowed to reach room temperature and remain overnight. The mixture was partitioned between an aqueous ammonium chloride solution (20 mL) and MTBE (50 mL) and extracted with EtOAc. The combined organic solutions were dried over Na2SO4 and evaporated under vacuum to give 0.075 g of crude product, which was purified by preparative HPLC to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(methyl-d3)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide as a single diastereomer (15.4 mg, 39.0 μmol, 24% yield). MS calculation: C20H20D3ClFN3O2: 394.2; Measured: 395.2 [M+1]+; 1H NMR (400MHz, methanol-d4): δ 7.89 (dd, J = 6.7, 2.6Hz, 1H), 7.66 (s, 1H), 7.52 (ddd, J = 9.0, 4.2, 2.6Hz, 1H), 7.25 (t, J = 8.9Hz, 1H), 3.77 (s, 3H), 3.36 (s, 1H), 2.61-2.45 (m, 2H),2.31-2.19(m,2H), 1.88(dd,J=12.6,8.0Hz,2H), 1.73(td,J=12.3,8.7Hz,2H), 1.61(dd,J=12.6,6.7Hz,2H)ppm.

[0568] Synthesis of Examples 81 to 113. Examples 81 to 113 in Table 6 were synthesized using the corresponding starting materials according to the procedures provided above.

[0569] Table 6. Examples 81 to 113 Specification 81 / 163 pages 84 CN 121248511 A

[0570] Specification 82 / 163 pages 85 CN 121248511 A

[0571] Specification 83 / 163 pages 86 CN 121248511 A

[0572] Specification 84 / 163 pages 87 CN 121248511 A

[0573] Specification 85 / 163 pages 88 CN 121248511 A

[0574] Specification 86 / 163 pages 89 CN 121248511 A

[0575] Specification 87 / 163 pages 90 CN 121248511 A

[0576] Specification 88 / 163 pages 91 CN 121248511 A

[0577] Specification page 89 / 163, page 92, CN 121248511 A

[0578] Specification page 90 / 163, page 93, CN 121248511 A

[0579] Specification page 91 / 163, page 94, CN 121248511 A

[0580] Specification page 92 / 163, page 95, CN 121248511 A

[0581] Specification page 93 / 163, page 96, CN 121248511 A

[0582] Specification page 94 / 163, page 97, CN 121248511 A

[0583] Specification page 95 / 163, page 98, CN 121248511 A

[0584] Specification page 96 / 163, page 99, CN 121248511 A

[0585]

[0586] Example 114 Specification 97 / 163 pages 100 CN 121248511 A

[0587]

[0588] N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. : To 4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazol (5.8g)t-BuLi (1.3M, 19.5mL, 25.0mmol) was added dropwise to a solution of N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (940.0mg, 2.5mmol) in ... The mixture was quenched with NH4Cl solution (3 mL) and concentrated under vacuum to give a crude product, which was purified by column chromatography to give N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (600.0 mg, 46%), a white solid, as a single diastereomer. MS calculation: C24H24ClF4N5O2: 525.2; Measured: 525.9 [M+1]+; 1H NMR (400MHz, d6-DMSO): δ 10.23 (s, 1H), 7.96 (dd, J=6.8, 2.0Hz, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.61–7.54 (m, 1H), 7.41 (t, J=9.2Hz, 1H), 4.87 (s, 1H), 3.83 (s, 3H), 3.68 (s, 3H), 3.28–3.17 (m, 1H), 2.48–2.41 (m, 2H), 2.41–2.03 (m, 4H) ,1.93-1.77(m,4H)ppm.

[0589] Example 115

[0590]

[0591] N-(3-cyano-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide. Zn(CN)₂ (1.7 g, 14.0 mmol), t-BuXPhos (300.0 mg, 0.7 mmol), and a third-generation t-BuXPhos precatalyst (560.0 mg, 0.7 mmol) were added to a solution of N-(3-chloro-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (740.0 mg, 1.4 mmol) in dioxane / H₂O (45 mL, v / v = 2:1). The reaction was stirred at 60 °C for 4 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat, washed with methanol, and concentrated.The crude product was obtained and purified by column chromatography and reversed-phase chromatography to obtain N-(3-cyano-4-fluorophenyl)-4-(5-hydroxy-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)octahydrocyclopentadien-2-yl)-1-methyl-1H-imidazol-5-carboxamide (270.0 mg, 37.3%), which is a white solid. TLC: 7% MeOH / DCM (Rf: 0.3); MS calculation: C25H24F4N6O2: 516.2; Measured: 517.0 [M+1]+, 499.0 [M-18+1]+; 1H NMR (400MHz, CD3OD): δ 8.09 (dd, J=5.6, 2.8Hz, 1H), 7.91-7.81 (m, 1H), 7.66 (s, 1H), 7.65 (s, 1H), 7.37 (t, J=9.2Hz, 1H), 3.86 (s, 3H), 3.77 (s, 3H), 3.37-3.33 (m, 1H), 2.60-2.54 (m, 2H) ,2.34-2.29(m,2H) ,2.27-2.20(m,2H) ,1.94-1.89(m,4H)ppm. Specification 98 / 163 pages 101 CN 121248511 A

[0592] Intermediate 31

[0593]

[0594] N-(3-cyano-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazol-5-carboxamide. tBuXPhos-Pd-G3 (6.3 g, 8 mmol) and t-BuXPhos (3.4 g, 8 mmol) were added to a solution of Zn(CN)2 (9.4 g, 80 mmol) and N-(3-chloro-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (6 g, 16 mmol) in dioxane (250 mL) under N2 conditions. The mixture was stirred overnight at 85 °C. It was then cooled, filtered, washed with EA, and the organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography using 1–5% MeOH / DCM (v / v) to give N-(3-cyano-4-fluorophenyl)-1-methyl-4-(5-oxooctahydrocyclopentadien-2-yl)-1H-imidazolium-5-carboxamide (4 g, 68%), which was a yellow solid. TLC: 5% EtOH / DCM (Rf: 0.5); MS calculation: C20H19FN4O2: 366.1; actual: 367.1 [M+1]+.

[0595] Synthesis of Examples 116 to 222. Examples 116 to 222 in Table 7 were synthesized using the corresponding starting materials according to the procedures provided above.

[0596] Table 7. Examples 116 to 222

[0597] Specification 99 / 163 pages 102 CN 121248511 A

[0598] Specification 100 / 163 pages 103 CN 121248511 A

[0599] Specification 101 / 163 pages 104 CN 121248511 A

[0600] Specification 102 / 163 pages 105 CN 121248511 A

[0601] Specification 103 / 163 pages 106 CN 121248511 A

[0602] Specification 104 / 163 pages 107 CN 121248511 A

[0603] Specification 105 / 163 pages 108 CN 121248511 A

[0604] Specification 106 / 163 pages 109 CN 121248511 A

[0605] Specification 107 / 163 pages 110 CN 121248511 A

[0606] Specification 108 / 163 pages 111 CN 121248511 A

[0607] Specification 109 / 163 pages 112 CN 121248511 A

[0608] Specification 110 / 163 pages 113 CN 121248511 A

[0609] Specification 111 / 163 pages 114 CN 121248511 A

[0610] Specification 112 / 163 pages 115 CN 121248511 A

[0611] Specification 113 / 163 pages 116 CN 121248511 A

[0612] Specification 114 / 163 pages 117 CN 121248511 A

[0613] Specification 115 / 163 pages 118 CN 121248511 A

[0614] Specification 116 / 163 pages 119 CN 121248511 A

[0615] Specification 117 / 163 pages 120 CN 121248511 A

[0616] Specification 118 / 163 pages 121 CN 121248511 A

[0617] Specification 119 / 163 pages 122 CN 121248511 A

[0618] Specification 120 / 163 pages 123 CN 121248511 A

[0619] Specification 121 / 163 pages 124 CN 121248511 A

[0620] Specification 122 / 163 Page 125 CN 121248511 A

[0621] Specification page 123 / 163, page 126, CN 121248511 A

[0622] Specification page 124 / 163, page 127, CN 121248511 A

[0623] Specification page 125 / 163, page 128, CN 121248511 A

[0624] Specification page 126 / 163, page 129, CN 121248511 A

[0625] Specification page 127 / 163, page 130, CN 121248511 A

[0626] Specification page 128 / 163, page 131, CN 121248511 A

[0627] Specification page 129 / 163, page 132, CN 121248511 A

[0628] Specification page 130 / 163, page 133, CN 121248511 A

[0629] Specification 131 / 163 pages 134 CN 121248511 A

[0630] Specification 132 / 163 pages 135 CN 121248511 A

[0631] Specification 133 / 163 pages 136 CN 121248511 A

[0632] Specification 134 / 163 pages 137 CN 121248511 A

[0633] Specification 135 / 163 pages 138 CN 121248511 A

[0634] Specification 136 / 163 pages 139 CN 121248511 A

[0635] Specification 137 / 163 pages 140 CN 121248511 A

[0636] Specification 138 / 163 Page 141 CN 121248511 A

[0637] Specification 139 / 163 Page 142 CN 121248511 A

[0638] Specification 140 / 163 Page 143 CN 121248511 A

[0639] Specification 141 / 163 Page 144 CN 121248511 A

[0640] Specification 142 / 163 Page 145 CN 121248511 A

[0641] Specification 143 / 163 Page 146 CN 121248511 A

[0642] Specification 144 / 163 Page 147 CN 121248511 A

[0643] Specification 145 / 163 Page 148 CN 121248511 A

[0644] Instruction manual, pages 146 / 163, 149 CN121248511 A

[0645] Specification 147 / 163 pages 150 CN 121248511 A

[0646] Specification 148 / 163 pages 151 CN 121248511 A

[0647] Specification 149 / 163 pages 152 CN 121248511 A

[0648] Specification 150 / 163 pages 153 CN 121248511 A

[0649]

[0650] VI. Biodata

[0651] Measurement of the activity of the test compound against viruses produced by HepAD38 cells Specification 151 / 163 pages 154 CN 121248511 A

[0652] In growth medium (DMEM / F12 (1:1) (Hyclone, cat#:SH30023.02) HepAD8A cells grown in T-150 flasks (Corning, catalog number: 430825) containing 1X penicillin / streptomycin (Invitrogen, catalog number: 15140-122), 10% FBS (Tissue Culture Biologics, catalog number: 101), 250 μg / mL G418 (Alfa Aesar, catalog number: J62671), and 1 μg / mL tetracycline (Teknova, catalog number: T3320) were isolated using 0.25% trypsin-EDTA (Invitrogen, catalog number: 25200-056). Tetracycline-free treatment medium (15 mL DMEM / F12 (1:1), 1x penicillin / streptomycin, containing 2% FBS, approved Tet system (Clontech, catalog number: 631106)) was then added to the mixture and transferred to 50 mL conical tubes (Falcon, catalog number: 21008-918), and then rotated at 1300 rpm for 5 min. The clumps of cells were then resuspended / washed twice with 50 mL 1X DPBS (Invitrogen, catalog number: 14190-136) and resuspended / washed twice with 50 mL treatment medium. HepAD38 cells were then resuspended in 10 mL treatment medium, rinsed with a syringe, and counted. 50,000 cells / well were seeded in 180 μL of treatment medium in 96-well clear-bottom TC plates (Corning, catalog number: 3904), with 20 μL added. 10% DMSO (Sigma, catalog number: D4540) was used as a control, or the test compound was added to 10% DMSO in a 10X solution in the treatment medium to bring the final compound concentration to 10 μM. The plates were incubated in a 5% CO2 incubator at 37°C for 5 days.

[0653] Subsequently, viral load was determined by quantitative PCR (qPCR) of the HBV core sequence. A PCR reaction mixture was prepared containing the forward primer HBV-f 5'-CTGTGCCTTGGGTGGCTTT-3' (IDT DNA), the reverse primer HBV-r 5'-AAGGAAAGAAGTCAGAAGGCAAAA-3' (IDT DNA), the fluorescent TaqMantm probe HBV probe 5'-FAM / AGCTCCAAA / ZEN / TTCTTTATAAGGGTCGATGTC / 3IABkFQ-3' (IDT DNA), 10 μL / well qPCR (Quanta Biosciences, catalog number: 95114-05K), and 6 μL / well DEPC water (Alfa Aesar, catalog number: J62087). 4 μL of supernatant was added to a 16 μL reaction mixture in a qPCR plate (Applied Biosystems, catalog number: 4309849), sealed with a membrane (Applied Biosystems, catalog number: 4311971), centrifuged for a few seconds, and then run on an Applied Biosystems VIIA7. The PCR mixture was incubated at 45°C for 5 min, then at 95°C for 10 min, followed by 40 cycles of incubation at 95°C for 10 sec and at 60°C for 20 sec. Viral load was quantified using ViiATM7 software according to known HBV DNA standards. The viral load from the supernatant of wells containing treated cells was compared with the viral load from the supernatant of DMSO control wells (≥3 cells / plate). Cell viability was measured using a modified CellTiter-Glo luminescent cell viability assay (Promega, catalog number: G7573). Mix an appropriate amount of CellTiter-Glo (CTG) 1X DPBS at a 1:1 ratio, add 100 μL of the mixture to each well, and then completely remove all supernatant from each well without touching the cell surface. Incubate the plate at room temperature on an orbital shaker for 10 minutes, and then read the plate using a microplate reader (TECAN M1000 or Envision). The EC50 or CC50 values ​​were calculated by curve fitting using a four-parameter nonlinear logistic regression model (GraphPad Prism or Dotmatics). All CC50 values ​​were >10 μM.

[0654] Table 8 shows the viral load reduction EC50 values ​​of the exemplary compounds of the present invention grouped into the following ranges: A represents EC50 <10 nM; B represents EC50 ≥10 to <50 nM; C represents EC50 ≥50 to <500 nM.

[0655] Table 8. Viral load reduction of exemplary compounds of the present invention Specification 152 / 163 pages 155 CN 121248511 A

[0656] Specification 153 / 163 pages 156 CN 121248511 A

[0657] Specification 154 / 163 pages 157 CN 121248511 A

[0658] Specification 155 / 163 pages 158 CN 121248511 A

[0659] Specification 156 / 163 pages 159 CN 121248511 A

[0660] Specification 157 / 163 pages 160 CN 121248511 A

[0661] Specification 158 / 163 pages 161 CN 121248511 A

[0662] Specification 159 / 163 pages 162 CN 121248511 A

[0663]

[0664] VII. Stereochemistry of the Examples

[0665] AIA-225 Specification 160 / 163 pages 163 CN 121248511 A

[0666]

[0667] 5-Amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5-(methylthiomethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide. To a solution of 5-amino-N-(3-chloro-4-fluorophenyl)-3-(hexahydro-1'H-spiro[ethylene oxide-2,2'-cyclopentadienyl]-5'-yl)-1-methyl-1H-pyrazole-4-carboxamide (200 mg, 0.495 mmol), NaSMe (138.6 mg, 1.98 mmol) was added to THF / H2O (6 mL / 2 mL). The mixture was stirred overnight at room temperature. The solvent was removed, and the crude product was purified by silica gel column chromatography using 3:1 (v / v) petroleum ether / ethyl acetate to give 5-amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5-(methylthiomethyl)octahydrocyclopentadienyl-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 44.7%) as a yellow solid. MS (m / z): Calculated: 452.1, Measured: 452.2 [M+1]+.

[0668] AIA-227-1, AIA-227-2

[0669]

[0670] 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2r,5r)-5-hydroxy-5-(methylsulfonylmethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (AIA-227-1) and 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methylsulfonylmethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (AIA-227-2). m-CPBA (114.8 mg, 0.66 mmol) was added to a solution of 5-amino-N-(3-chloro-4-fluorophenyl)-3-(5-hydroxy-5-(methylthiomethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (100 mg, 0.22 mmol) in DCM (5 mL). The mixture was stirred overnight at room temperature. The solvent was removed, and the crude material was purified by silica gel column chromatography using 3:1 (v / v) DCM / MeOH to give AIA-227 (40 mg, 37.3%) as a white solid. MS (m / z): Calculated: 484.1, Measured: 484.3 [M+1]+. AIA-227 was separated by SFC to obtain AIA-227-1 (4 mg), which is a white solid, and AIA-227-2 (4 mg), which is a white solid. AIA‑227‑1:1H NMR (400MHz, DMSO‑d6): δ8.95(s,1H) ,7.91(dd,J=6.8,2.4Hz,1H) ,7.54‑7.50(m ,1H) ,7.35(t,J=9.2Hz,1H) ,5.97(s ,2H) ,4.79(s ,1H) , 3.59‑3.53(m,1H) ,3.49(s,3H) ,3.35(s,2H) ,2.97(s,3H) ,2.67‑2.60(m,2H) ,2.18‑2.12(m, 2H) ,2.07-2.02(m,2H) 1.45–1.36 ppm (m, 4H). AIA-227-2: 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 7.91 (dd, J = 2.8, 2.4 Hz, 1H), 7.53–7.49 (m, 1H), 7.34 (t, J = 9.2 Hz, 1H), 5.97 (s, 2H), 4.87 (s, 1H), 3.49 (s, 3H), 3.43–3.35 (m, 1H), 3.25 (s, 2H), 2.97 (s, 3H), 2.49 (s, 2H). (Instruction manual, pages 161 / 163, 164, CN 121248511 A) 2.15–2.09 (m, 2H), 2.02–1.97 (m, 2H), 1.73–1.60 (m, 4H) ppm. AIA-227-2

[0671]

[0672] 5-Amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methylsulfonylmethyl)octahydrocyclohexaneAlternative Synthesis of Pentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide. n-BuLi (327.5 mL, 818.7 mmol, 2.5 M) was added dropwise to a solution of dimethyl sulfoxide (77.0 g, 818.7 mmol) in THF (800 mL) at -78 °C. The resulting solution was heated to -20 °C and stirred for 1 h. The reaction mixture was cooled to -78 °C and AIA-002 (40.0 g, 102.3 mmol) in anhydrous tetrahydrofuran (1200 mL) was added over 2 hours. The mixture was heated to room temperature and stirred for another 4 h. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (200 mL). The solvent was removed, followed by dilution with water, extraction with ethyl acetate (3 x 200 mL), drying to Na₂SO₄, filtration, and concentration to give the crude product. The crude product was purified by column chromatography using 0–5% (v / v) methanol / DCM and basic preparative HPLC to give 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methanesulfonylmethyl)octahydrocyclopentadien-2-yl)-1-methyl-1H-pyrazole-4-carboxamide (26.0 g, 52.4%), which was a white solid. MS (m / z): Calculated: 484.1, Measured MS: 485.2 [M+1]+; 1H NMR (400MHz, DMSO-d6): δ 8.96 (s, 1H), 7.92 (dd, J=6.8, 2.8Hz, 1H), 7.54-7.50 (m, 1H), 7.35 (t, J=8.8Hz, 1H), 5.98 (s, 2H), 4.88 (s, 1H), 3.49 (s, 3H), 3.42-3.37 (m, 1H), 3.25 (s, 2H), 2.97 (s, 3H), 2.15-2.10 (m, 2H), 2.03-1.97 (m, 2H) ,1.73-1.60(m,4H)ppm.

[0673] After 20 days of volatilization, a crystal of compound AIA-227-2 with a size of 0.08x0.10x0.20mm was obtained from EtOH and used for X-ray diffraction data collection. Data were collected at room temperature using CuKα radiation in ω / φ scan mode on a Bruker SMART CCD surface detector diffractometer. 10846 reflections were collected, of which 3754 reflections were unique (Rint = 0.0507).

[0674] The crystal belongs to the monoclinic system with space group P21 / c. The cell parameters are as follows: a = 6.6143(3), b = 14.0381(8), α = γ = 90.0°, β = 97.702(3), Z = 4.

[0675] The structure was solved using a direct method, and all non-H atoms were refined using the SHELXTL program with full matrix least squares. All H atoms were placed in geometrically ideal positions and confined to their parent atoms. A multi-scan absorption correction method was used, and the maximum and minimum transmission parameters were 0.7531 and 0.6017, respectively. The final R1, wR2, and GOF were 0.0457, 0.1293, and 1.024, respectively.

[0676] A C21H26FClN4O4 molecule exists in the asymmetric unit, and hydrogen bonds exist between them, which plays an important role in the stable stacking of the crystal structure.

[0677] The ORTEP plot of compound AIA-227-2 is presented in Figure 1. The relative stereochemical scheme of compound AIA-227-2 is shown in Figure 2. The stereochemical description of the chemical structure of the related embodiments is based on this.

[0678] Incorporation by Reference

[0679] All publications and patents mentioned herein, including the items listed below, are incorporated herein by reference in their entirety for all purposes, as if each individual publication or patent were specifically and individually incorporated by reference. In case of conflict, the application, including any definition herein, shall prevail.

[0680] Equivalent Specification 162 / 163 pages 165 CN 121248511 A

[0681] Although specific embodiments of the present disclosure have been discussed, the above description is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the present disclosure should be determined by reference to the full scope of the claims together with their equivalents and the description together with such variations.

[0682] Unless otherwise stated, all figures for amounts of expressed ingredients, reaction conditions, etc., used in the description and claims should be understood to be modified in all cases by the term “about”. Therefore, unless otherwise stated, the numerical parameters set forth in this specification and the appended claims are approximate values ​​and may vary depending on the desired properties sought through this disclosure. Specification 163 / 163 pages 166 CN 121248511 A Figure 1 Figure 2 Specification Drawings 1 / 1 page 167 CN 121248511 A SP2616005 5-MEMBERED HETEROARYL CARBOXAMIDE COMPOUNDS FOR TREATMENT OF HBV Abstract The present disclosure provides, in part, 5-membered heteroaryl carboxamide compounds, andpharmaceutical compositions thereof, useful for disruption of HBV core protein assembly, and methods of treating Hepatitis B (HBV) infection. Abstract

Claims

1. A compound of formula I, Or its pharmaceutically acceptable salt, wherein: L is C 1-4 Alkylene or halogenated C 1-4 Alkylene; L 1 and L 2 Independent as key, C 1-6 Alkylene, O, NR c C(O), C(O)O, C(O)NR c S(O) t Or S(O) t NR c ; X 1 It is NR x1 ; X 3 is CR 4 R 8 ; X 4 and X 6 Independently represented by O or S; X 5 Is it O, S, or NR? 0 ; R a R b and R c Each time it appears, it is independently selected from the following group: hydrogen, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 3-6 Monocycloalkyl; R d It is hydrogen, OH, C 1-6 Alkyl or C 1-6 Alkoxy; R x1 It is hydrogen, C 1-4 Alkyl, C 1-4 alkenyl, C 1-4 alkynyl, halogenated C 1-4 Alkyl or C 3-6 Monocycloalkyl; or R x1 and R 2 Together they form -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2O-, -CH2OCH2-, -CH2CH2CH2O-, -CH2CH2OCH2-, -CH2CH2-NH-, -CH2NHCH2-, -CH2CH2CH2NH-, or -CH2CH2NHCH2- groups; R 0a Each time it appears, it is independently selected from the following group: hydrogen, halogen, OH, CN, NO2, R a R b N-, C 1-4 Alkyl and Halogenated C 1-4 alkyl; R 4a and R 6a Independent of hydrogen or C 1-4 alkyl; R 0 R 6 and R 11 Each time it appears, it is independently selected from the following groups: hydrogen, halogen, OH, CN, NO2, oxo, R d N=, hydrazine, formyl, azide, silyl, siloxy, HOC(O)-, R a R b N-, R a R b NS(O) t -、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl-, R a R b NC 1-6 Alkyl-, HOC(O)C 1-6 Alkyl-, R a R b NC 1-6 Alkyl NR c -、C 1-6 Alkyl NR a C 1-6 Alkyl NR c -、C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy-, R a R b NC 1-6 Alkoxy-, C 1-6 Alkoxy C 1-6 Alkyl-, Halogenated C 1-6 Alkoxy C 1-6 Alkyl-, R a R b NC(O)-, C 1-6 Alkyl C(O)-, C 1-6 Alkoxy C(O)-, C 1-6 Alkyl C(O)O-, C 1-6 Alkyl S(O) q -、C 1-6 Alkyl S(O) t NR c -、C 1-6 Alkyl S(O) t C 1-6 Alkyl-, C 1-6 Alkyl S(O) t NR a C 1-6 Alkyl-, C 3-6 Cycloalkyl S(O) t C 1-6 Alkyl-, C 1-6 Alkyl C(O)C 1-6 Alkyl- and C 1-6 Alkyl C(O)OC 1-6 alkyl-; R 1 It is a phenyl or a 5- to 6-membered monocyclic heteroaryl group, wherein the phenyl or 5- to 6-membered monocyclic heteroaryl group is optionally composed of one, two, or three independently selected R groups. 11 Group substitution; R 2 and R 8 Independently selected from the following groups: hydrogen, halogen, CN, OH, R a R b N, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 3-5 Monocycloalkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy; R 3 yes R 4 It is R 5 -L 1 -、R 6 or R 9 ; R 5 yes R 9 is R 14 S(O) q -L-, R 14 S(O) q NH-L- or R 14 C(O)NH-L-; R 14 It is R a R b N-, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or R 5 -L 1 -; q, r, t, and w are each independently selected from 0, 1, and 2 when they appear; and v is independently selected from 0, 1, 2, and 3 each time it appears.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R x1 It is either hydrogen or methyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein r is 0.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: R 1 yes R 11 Each time it appears, it is independently selected from the following group: halogen, CN, C. 1-6 Alkyl and Halogenated C 1-6 Alkyl; and z1 is 0, 1, 2 or 3.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 3 yes 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 4 It is R 6 R 5 -L 1 -or R 9 .

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein L 1 It is a key.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for treating hepatitis B (HBV) infection.

Images