HIV inhibitor compound

Abstract

The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof as described herein. The present invention also provides a pharmaceutical composition comprising a compound of formula I, a method for preparing a compound of formula I, and the use of a compound of formula I in a method of treatment for treating HIV viral proliferation, treating AIDS or delaying the onset of AIDS symptoms in a mammal. Preferred compounds are N-[(2S)-1-[2-[(2S,3S)-2-hydroxy-3-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoyl]amino]-4-phenylbutyl]-2-[(phenyl)methyl]hydrazino]-3,3-dimethyl-1-oxobutan-2-yl]carbamate atazanavir (ATV) analogues substituted by a number of heterocycles, such as pyrazole (R1); such as oxetane (substituent of X2); such as pyridine or pyrimidine (X1); such as piperazine or 3,8-diazabicyclo[3.2.1]octane (X2).

Description

[0001] This application is a divisional application of the patent application with the filing date of February 5, 2018, application number 201880023198.1, and title "HIV Inhibitor Compounds".

[0002] Cross - Reference to Related Applications

[0003] This patent application claims the benefit of the priority of U.S. Provisional Patent Application Serial No. 62 / 455,348, filed on February 6, 2017. The content of this application is incorporated herein by reference. Technical Field

[0004] The present disclosure relates to novel compounds for the treatment of retroviral infections, including those caused by the HIV virus. The present disclosure also relates to intermediates for their preparation and pharmaceutical compositions containing these compounds. Background Art

[0005] Human immunodeficiency virus (HIV) infection and related diseases are major public health problems worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Several protease inhibitors (PIs) have been approved for AIDS or HIV. However, many PI inhibitors have a high hepatic metabolic rate, which may require co-administration of enhanced doses or more frequent doses. In addition, viral resistance remains a problem. Therefore, there is a need for new agents that inhibit HIV replication. Summary of the Invention

[0006] The present disclosure provides compounds and methods for the treatment of HIV infection. Thus, in one embodiment, the present invention provides a compound of formula I:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] R 1 is a 5- to 10-membered heterocycle having 1 to 5 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered heterocycle or 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R a groups;

[0010] R 2 and R 3 are each independently C 1-4 alkyl, C 3-6 cycloalkyl, O-R 2A , C 1-2 alkyl-O-R2A , N-(R 3A )2 or C 1-2 -alkyl-N-(R 3A )2,

[0011] where each R 2A is independently C 1-4 -alkyl, C 3-6 -cycloalkyl or a 4- to 10-membered heterocyclic group having 1 to 5 heteroatoms selected from N, O and S,

[0012] where each R 3A is independently hydrogen, C 1-4 -alkyl, C 3-6 -cycloalkyl or COO(R e ),

[0013] and where each C 3-6 -cycloalkyl or 4- to 10-membered heterocyclic group is optionally substituted with 1 to 3 R f groups, where each R f is independently C 1-2 -alkyl or halogen;

[0014] R 4 is hydrogen, halogen, C 1-4 -alkyl, C 1-4 -haloalkyl, C 3-6 -cycloalkyl, C 1-4 -alkoxy or C 1-4 -haloalkoxy;

[0015] R 7 is hydrogen, halogen, C 1-4 -alkyl, C 1-4 -haloalkyl, C 3-6 -cycloalkyl, C 1-4 -alkoxy or C 1-4 -haloalkoxy;

[0016] R 5 , R 6 , R 8 and R 9 are each independently hydrogen, halogen, C 1-2 -alkyl, C 1-2 -haloalkyl or C 3-6 -cycloalkyl;

[0017] and where two or more of R 4 , R 5 and R 6 , or two or more of R 7 , R 8 and R 9 are optionally joined together to form one or more C3-6 A cycloalkyl group, optionally substituted with 1 to 4 groups selected from halogen, C 1-2 alkyl and C 1-2 haloalkyl;

[0018] Each R 10 is independently halogen, cyano, C 1-4 alkoxy, C 1-6 alkyl or C 3-6 cycloalkyl;

[0019] n is from 0 to 4;

[0020] Each R a is independently halogen, C 1-4 alkyl, C 1-4 alkyl having 1 to 2 groups selected from hydroxy and C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, an optionally R a1 substituted 4- to 10-membered heterocyclic group having 1 to 5 heteroatoms selected from N, O and S, or O-R 3B ,

[0021] wherein R 3B is an optionally R a1 substituted C 3-6 cycloalkyl or an optionally R a1 substituted 4- to 10-membered heterocyclic group having 1 to 5 heteroatoms selected from N, O and S,

[0022] wherein each R a1 is independently C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl or a 4- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S;

[0023] A is ethynyl or a bond;

[0024] X 1 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, wherein the 6- to 10-membered aryl or 5- to 10-membered heteroaryl is each optionally substituted with 1 to 4 R b groups;

[0025] X 2 is hydrogen or a 4- to 10-membered heterocyclic group having 1 to 5 heteroatoms selected from N, O and S, wherein the 4- to 10-membered heterocyclic group is optionally substituted with one R 11 and optionally substituted with 1 to 5 R b groups;

[0026] R 11 is C═O(R c ), CH2(R d ), S(O) 1-2 (C 1-4 alkyl), S(O) 1-2 C 3-6 cycloalkyl, a 4- to 10-membered heterocyclic group having 1 to 5 heteroatoms selected from N, O, and S, or a 5- to 9-membered heteroaryl group having 1 to 5 heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclic group or the 5- to 9-membered heteroaryl group is each optionally substituted by 1 to 5 R b groups;

[0027] Each R b is independently halogen, oxo, C 1-4 alkyl, C 1-4 alkyl having 1 to 2 groups selected from hydroxy and C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkoxy or COO(R e );

[0028] R c is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, N(R e )2, C 3-6 cycloalkyl or a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S, wherein the C 3-6 cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by 1 to 5 R b groups;

[0029] R d is COO(R e ), N(R e )2, C 3-6 cycloalkyl or a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S, wherein the C 3-6 cycloalkyl and the 4- to 6-membered heterocyclic group are each optionally substituted by 1 to 5 R b groups;

[0030] Each R 12 is C 1-2 alkyl, halogen, -OC 1-2 alkyl or cyano;

[0031] Each p is from 0 to 4;

[0032] And each R e is independently hydrogen or C1-4 Alkyl

[0033] There is also provided a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition further comprises one, two, three or four additional therapeutic agents.

[0034] There is also provided a method of treating or preventing human immunodeficiency virus (HIV) infection, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0035] In certain embodiments, the present disclosure relates to an article of manufacture comprising a unit dose of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0036] There is also provided a compound disclosed herein or a pharmaceutically acceptable salt thereof for use in therapy.

[0037] There is also provided a compound disclosed herein or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing human immunodeficiency virus (HIV) infection, said method comprising administering to a subject in need thereof a therapeutically effective amount of said compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 Predicted hepatic clearances for certain compounds and reference compounds are described, as more fully described in the biological examples herein.

[0039] Figure 2 Graphs of IV dog pharmacokinetic studies for certain compounds and reference compounds, and tables summarizing the IV and oral PK data for these compounds, are described, as more fully described in the examples herein.

[0040] Figure 3 Graphs of IV rat pharmacokinetic studies for certain compounds and reference compounds, and tables summarizing the IV and oral PK data for these compounds, are described, as more fully described in the examples herein.

[0041] Figure 4 Fold changes of certain clinically isolated strain resistance mutations for certain compounds and reference compounds relative to wild type are described, as more fully described in the examples herein.

[0042] Figure 5 Resistance breakthroughs for certain compounds and reference compounds are described, as more fully described in the examples herein. DETAILED DESCRIPTION

[0043] The following is a list of abbreviations and acronyms used throughout the application:

[0044] Abbreviation Meaning

[0045] °C Degrees Celsius

[0046] ATP Adenosine-5'-triphosphate

[0047] AcOH Acetic acid

[0048] d Doublet

[0049] dd Double doublet

[0050] DCE 1,2-Dichloroethane

[0051] DCM Dichloromethane

[0052] DIPEA N,N-Diisopropylethylamine

[0053] DME 1,2-Dimethoxyethane

[0054] DMF Dimethylformamide

[0055] DMSO Dimethyl sulfoxide

[0056] dppf 1,1'-Bis(diphenylphosphino)ferrocene

[0057] EGTA Ethylene glycol tetraacetic acid

[0058] ETOAC Ethyl acetate

[0059] equiv / eq Equivalent

[0060] ESI Electrospray ionization

[0061] Ac Acetate(salt)

[0062] Et Ethyl

[0063] g Gram

[0064] HATU 2-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0065] hERG Human Ether-à-go-go related gene

[0066] HPLC High performance liquid chromatography

[0067] h / hr Hour

[0068] Hz Hertz

[0069] IC 50 Half maximal inhibitory concentration

[0070] J coupling constant

[0071] Kg Kilogram

[0072] M Mole

[0073] m Multiplet

[0074] m / z Mass-to-charge ratio

[0075] M+ Mass peak

[0076] M+H Mass peak plus hydrogen

[0077] Me Methyl

[0078] MeOH Methyl alcohol / Methanol

[0079] mg Milligram

[0080] MHz Megahertz

[0081] min / m Minute

[0082] ml / mL Milliliter

[0083] mM Millimole

[0084] mmol Millimole

[0085] MS Mass spectrometry

[0086] mw Microwave

[0087] N Standard

[0088] mol Mole

[0089] NMP N-Methylpyrrolidone

[0090] NMR Nuclear magnetic resonance

[0091] Ph Phenyl

[0092] ppm Parts per million

[0093] prep Preparative

[0094] Rf Retention factor

[0095] RP Reverse phase

[0096] RT / rt Room temperature

[0097] s Second

[0098] s Singlet

[0099] t Triplet

[0100] TEA Triethylamine

[0101] TFA Trifluoroacetic acid

[0102] TLC Thin layer chromatography

[0103] TMS Trimethylsilyl

[0104] WT Wild type

[0105] δ Chemical shift

[0106] μg Microgram

[0107] μL / μl Microliter

[0108] μM Micromole

[0109] μm Micrometer

[0110] μmol Micromole

[0111] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" as used herein and in the appended claims include plural referents. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays known to those skilled in the art and their equivalents, and so forth.

[0112] For convenience, a dash is added at the front or end of a chemical group; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group, e.g.:

[0113] A dashed line represents an optional bond. When multiple substituents are identified, the point of attachment is on the terminal substituent (e.g., for "alkylaminocarbonyl", the point of attachment is on the carbonyl substituent).

[0114] The prefix "C x-y " represents the following groups having x (e.g., 1) to y (e.g., 6) carbon atoms, and in certain groups (such as heteroalkyl, heteroaryl, heteroarylalkyl, etc.), one or more carbon atoms may be replaced by one or more heteroatoms or heteroatom groups. For example, "C 1-6 alkyl" represents an alkyl having 1 to 6 carbon atoms. Similarly, the term "x-y membered" ring (where x and y are numerical ranges, e.g., "3 to 12 membered heterocyclic group") refers to a ring containing x-y atoms (e.g., 3-12), where up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.

[0115] In addition, certain common alternative chemical names may or may not be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" or "arylene" groups, or alkylene (alkyl-yl) groups, "arylene" groups or "aromaticylene" groups or arylene (arylyl) groups, respectively.

[0116] "Compounds disclosed herein" or "compounds of the present disclosure" refers to compounds of formula (I), (Ia), (Ib), (Ic), (Id), and / or (Ie). Specific compounds of Examples 1-245 are also included.

[0117] "Alkyl" refers to any group derived from a straight-chain or branched-chain saturated hydrocarbon. Alkyl includes, but is not limited to, methyl, ethyl, propyl such as prop-1-yl, prop-2-yl (isopropyl), butyl such as but-1-yl, but-2-yl (sec-butyl), 2-methyl-prop-1-yl (isobutyl), 2-methyl-prop-2-yl (tert-butyl), pentyl, hexyl, octyl, decyl, etc. Unless otherwise specified, alkyl has 1 to 10 carbon atoms, for example 1 to 6 carbon atoms, for example 1 to 4 carbon atoms.

[0118] "Alkenyl" refers to any group derived from a straight-chain or branched-chain hydrocarbon having at least one carbon-carbon double bond. Alkenyl includes, but is not limited to, vinyl (ethenyl), allyl (2-propenyl), 1-butenyl, 1,3-butadienyl, etc. Unless otherwise specified, alkenyl has 2 to 10 carbon atoms, for example 2 to 6 carbon atoms, for example 2 to 4 carbon atoms.

[0119] "Alkynyl" refers to any group derived from a straight-chain or branched-chain hydrocarbon having at least one carbon-carbon triple bond, and includes those groups having one triple bond and one double bond. Examples of alkynyl include, but are not limited to, ethynyl (-C≡C-), propargyl (-CH2C≡C-), (E)-pent-3-en-1-ynyl, etc. Unless otherwise specified, alkynyl has 2 to 10 carbon atoms, for example 2 to 6 carbon atoms, for example 2 to 4 carbon atoms.

[0120] "Amino" refers to –NH2. Amino can also be substituted as described herein, for example, by alkyl, carbonyl, or other amino groups. The term "alkylamino" refers to an amino group substituted by one or two alkyl substituents (e.g., dimethylamino or propylamino).

[0121] As used herein, the term "aryl" refers to a single fully carbon aromatic ring or multiple fused fully carbon ring systems, wherein at least one ring is aromatic. For example, in certain embodiments, an aryl has 6 to 20 carbon atoms, 6 to 14 carbon atoms or 6 to 12 carbon atoms. Aryl includes phenyl. Aryl also includes multiple fused ring systems having about 9 to 20 carbon atoms (e.g., a ring system containing 2, 3 or 4 rings), wherein at least one ring is aromatic and the other rings may be aromatic or non-aromatic (i.e., carbocyclic). Such multiple fused ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocyclic moiety of the multiple fused ring system. When valence requirements permit, the rings of the multiple fused ring systems can be connected to each other by fusion, spiro and bridge bonds. It should also be understood that when referring to a certain atomic range of a heteroaryl (e.g., 6-10 membered heteroaryl), the atomic range refers to the total ring atoms of the heteroaryl. For example, a 6-membered heteroaryl will include phenyl, and a 10-membered heteroaryl will include naphthyl and 1,2,3,4-tetrahydronaphthyl. Aryl includes, but is not limited to, those groups derived from: acenaphthene, anthracene, azulene, benzene, , cyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indane, perylene, benzo[a]naphthalene, phenanthrene, pyrene, etc. Non-limiting examples of aryl include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, etc.

[0122] "Bridged" refers to ring fusion where non-adjacent atoms on the ring are connected by a divalent substituent, such as an alkylene or heteroalkylene or a single heteroatom. Quinuclidinyl and adamantyl are examples of bridged ring systems.

[0123] The term "cycloalkyl" refers to a single saturated or partially unsaturated fully carbon ring having 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), e.g., 3 to 12 ring atoms, e.g., 3 to 10 ring atoms. The term "cycloalkyl" also includes multiple fused, saturated and partially unsaturated fully carbon ring systems (e.g., a ring system containing 2, 3 or 4 carbocyclic rings). Thus, cycloalkyl includes polycyclic carbocyclic rings, such as bicyclic carbocyclic rings (e.g., a bicyclic carbocyclic ring having about 6 to 12 ring carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocyclic rings (e.g., tricyclic and tetracyclic carbocyclic rings having up to about 20 ring carbon atoms). When valence requirements permit, the rings of the multiple fused ring systems can be connected to each other by fusion, spiro and bridge bonds. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, spiro[3.3]heptane and 1-cyclohex-3-enyl.

[0124] "Halogenated" and "halogen" refer to fluorine, chlorine, bromine and iodine.

[0125] "Halogenated alkyl" means an alkyl group in which one or more hydrogen atoms are each independently replaced by a halogen. Examples include, but are not limited to, –CH2Cl, –CH2F, –CH2Br, –CFClBr, –CH2CH2Cl, –CH2CH2F, –CF3, –CH2CF3, –CH2CCl3, etc., and alkyl groups such as perfluoroalkyl groups in which all hydrogen atoms are replaced by fluorine atoms.

[0126] "Alkoxy" or "alkoxyl" means a moiety of the formula -O-alkyl, where the alkyl moiety is as defined above. For example, C 1-4 Alkoxy means an alkyl moiety having 1 to 4 carbon atoms attached to oxygen. "Halogenated alkoxy" or "haloalkoxy" means a moiety of the formula -O-halogenated alkyl, where the halogenated alkyl moiety is as defined above. For example, C 1-4 Alkoxy means a halogenated alkyl moiety having 1 to 4 carbon atoms attached to oxygen.

[0127] "Heteroalkyl" means an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatoms or heteroatom groups. Heteroatoms include, but are not limited to, N, P, O, S, etc. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -PH-, -P(O)2-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or cycloheteroalkyl. Heteroalkyls include, but are not limited to, -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, -CH2NRCH3, -CH2OH, etc., where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or heteroaryl, each of which may optionally be substituted. Heteroalkyls contain 1 to 10 carbons and up to four heteroatoms, for example 1 to 6 carbons and 1 to 2 heteroatoms.

[0128] "Heteroaryl" means a monocyclic or polycyclic aryl group in which one or more aromatic carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatoms or heteroatom groups, as defined above. Polycyclic systems are included within the heteroaryl and may be attached to the heteroatom or aryl ring at a ring. Heteroaryl includes, but is not limited to, groups derived from the following: acridine, benzimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyridone, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolinizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, etc. Heteroaryl may have 5-12, 5-10 or 5-6 members.

[0129] As used herein, the term "heterocyclic group" or "heterocycle" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system having at least one heteroatom (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur) in the ring. Unless otherwise specified, the heterocyclic group has from 5 to about 20 ring atoms, such as from 3 to 12 ring atoms, such as from 3 to 10 ring atoms, such as from 5 to 10 ring atoms or such as from 5 to 6 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having from about 1 to 6 ring carbon atoms and from 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur. When valence requirements permit, the rings of a polyfused ring (e.g., bicyclic heterocyclic group) system may be connected to each other by fusion, spiro, and bridge bonds. Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, ethylene oxide (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, tetrahydro-2H-thiopyran 1,1-dioxide, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, etc. Heterocycles include spiro rings, such as aza- or oxo-spiroheptane. The heterocyclic group also includes a partially unsaturated ring system having one or more double bonds, including a fused ring system having one aromatic ring and one non-aromatic ring, but not a fully aromatic ring system. Examples include dihydroquinoline, such as 3,4-dihydroquinoline, dihydroisoquinoline, such as 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., indoline, isoindoline, isoindolinone (such as isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'-isoindoline]-3'-one, etc. Other examples of heterocycles include, for example, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonyl, and hexahydropyrazino[2,1-c][1,4]oxazinyl.

[0130] "Hydroxyl" and "hydroxy" are used interchangeably and denote -OH. "Oxo" refers to or When tautomers of a compound exist, the hydroxyl and oxo groups are interchangeable.

[0131] It should be understood that combinations of chemical groups may be used and would be recognized by one of ordinary skill in the art. For example, the group "hydroxyalkyl" refers to a hydroxyl group attached to an alkyl group. A large number of such combinations can be readily envisioned. Other examples of substituent combinations used herein include: C 1-6 alkylaminocarbonyl (e.g., CH3CH2NHC(O)-), C 1-6Alkoxycarbonyl (e.g., CH3O-C(O)-), 5-7 membered heterocyclic group-C 1-6 Alkyl (e.g., piperazinyl-CH2-), C 1-6 Alkylsulfonyl-5-7 membered heterocyclic group (e.g., CH3S(O)2-morpholinyl-), 5-7 membered heterocyclic group C 1-6 Alkoxy 5-7 membered heterocyclic group oxy, (4-7 membered heterocyclic group)-4-7 membered heterocyclic group (e.g., oxetanyl-pyrrolidinyl-), C 3-6 Cycloalkylaminocarbonyl (e.g., cyclopropyl-NH-C(O)-), 5-7 membered heterocyclic group-C 2-6 Alkynyl (e.g., N-piperazinyl-CH2C≡CCH 2- ) and C 6-10 Arylaminocarbonyl (e.g., phenyl-NH-C(O)-).

[0132] "Spiro" means a ring substituent connected by two bonds to the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents, respectively. When substituents (R-groups) are joined together (e.g., when R 7 and R 8 are joined together), they can be taken from the same point of attachment to form a spiro ring.

[0133] The phrase "meta (3) position relative to the A ring attachment point" refers to the position adjacent to a substituent on the ring (e.g., -CN) and is shown by an arrow below, where z represents a carbon atom or nitrogen:

[0134]

[0135] Similarly, para (4) position substitution refers to the attachment of a substituent at the position shown below relative to the attachment point (e.g., B ring):

[0136]

[0137] Similarly, ortho or 2-position refers to the attachment of a substituent at the position shown below relative to the attachment point:

[0138]

[0139] The compounds described herein include isomers, stereoisomers, etc. As used herein, the term "isomer" refers to different compounds having the same molecular formula but different arrangements and configurations of atoms. Similarly as used herein, the term "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention and includes geometric isomers. It is understood that substituents may be attached to the chiral centers of carbon atoms. Accordingly, the present invention includes the enantiomers, diastereomers or racemates of the compound.

[0140] The term "fused" refers to a ring that is joined to an adjacent ring.

[0141] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture.

[0142] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be determined as R or S. Resolved compounds of unknown absolute configuration can be designated as (+) or (-) according to the direction (right or left) in which they rotate plane-polarized light at the sodium D line wavelength. Certain compounds described herein contain one or more asymmetric centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry. The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and mixtures of intermediates. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If a compound contains a double bond, the substituents can be in the E or Z configuration. If a compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents can have a cis or trans configuration. All tautomeric forms are also intended to be included. To the extent that the compounds described herein are represented as having a specific stereochemistry, those skilled in the art will understand that such compounds may contain some detectable or undetectable levels of compounds that have the same structure but different stereochemistry.

[0143] "IC 95 " or "EC 95 " refers to the inhibitory concentration required to achieve 95% of the maximum desired effect, which in many cases is the inhibition of the HIV virus. This term is obtained using an in vitro assay that evaluates the concentration-dependent inhibition of wild-type HIV virus.

[0144] "IC 50 " or "EC 50"refers to the inhibitory concentration required to achieve 55% of the maximum desired effect, which, in many cases, is the inhibition of the HIV virus. This term is obtained using an in vitro assay that evaluates the concentration-dependent inhibition of wild-type HIV virus.

[0145] "IQ" or "inhibitory quotient" refers to the ratio between the trough drug concentration (C tau ) and the level of drug resistance of an HIV isolate determined by IC 95 (i.e., C tau / IC 95 ).

[0146] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials used in the preparation of pharmaceutical compositions suitable for veterinary or human use.

[0147] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0148] "Pharmaceutically acceptable salts" refer to salts of a compound that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound (or can be converted to a form having the desired pharmacological activity of the parent compound). Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, etc., as well as salts formed when an acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, alkaline earth metal ion, or aluminum ion; or a salt formed by coordination with an organic base such as diethanolamine, triethanolamine, N-methylglucosamine, etc. This definition also includes ammonium salts and substituted or quaternized ammonium salts. A representative non-limiting list of pharmaceutically acceptable salts can be found in S.M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, edited by R. Hendrickson, 21st Edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), page 732, Table 38-5, both publications are hereby incorporated herein by reference.

[0149] The present disclosure also provides prodrugs of the compounds disclosed herein. A "prodrug" is defined in the pharmaceutical art as a biologically inactive derivative of a drug, which is converted into the biologically active parent drug in the human body after administration according to some chemical or enzymatic pathways.

[0150] A "subject" refers to a human, a domestic animal (such as a dog and a cat), a farm animal (such as a cow, a horse, a sheep, a goat and a pig), a laboratory animal (such as a mouse, a rat, a hamster, a guinea pig, a pig, a pocket pet, a rabbit, a dog and a monkey), etc.

[0151] As used herein, "treating" or "treatment" is a method of obtaining a beneficial or desired result. For the purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms and / or reduction in the degree of symptoms and / or prevention of worsening of symptoms associated with a disease or disorder. In one embodiment, "treating" or "treatment" includes one or more of the following: a) inhibiting a disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder, and / or reducing the degree of the disease or disorder); b) slowing or preventing the development of one or more symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, delaying the worsening or progression of the disease or disorder); and / or c) alleviating the disease or disorder, e.g., causing the clinical symptoms to subside, improving the disease state, delaying the disease progression, improving the quality of life and / or prolonging the survival period.

[0152] As used herein, "delaying" the development of a disease or disorder means postponing, hindering, slowing, retarding, stabilizing and / or deferring the development of the disease or disorder. The delay can have different time lengths, depending on the history of the disease and / or the subject being treated. It will be apparent to those skilled in the art that a sufficient or significant delay can actually include prevention, since the subject does not develop the disease or disorder. For example, a method of "delaying" the development of AIDS, compared to not using the method, is a method of reducing the probability of disease development and / or reducing the degree of the disease within a given time frame. Such a comparison can be based on clinical studies using a statistically significant number of individuals. For example, known methods can be used to detect the development of AIDS, such as + confirming the HIV status of an individual and evaluating the individual's T cell count or other indicators of AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits or groin, or the presence of an opportunistic disease known to be associated with AIDS (e.g., a condition that does not exist in a subject with a normal immune system but does exist in an AIDS patient). Development can also refer to the progression of a disease that was initially undetectable, including occurrence, recurrence and onset.

[0153] As used herein, "prophylaxis" or "preventive" refers to a regimen that prevents the onset of a disease or disorder such that the clinical symptoms of the disease do not develop. Thus, "prophylaxis" involves administering a treatment (e.g., administering a therapeutic substance) to a subject before signs of the disease are detectable in the subject (e.g., administering a therapeutic substance to a subject in the absence of a detectable infectious agent (e.g., a virus)). The subject can be a subject at risk of developing a disease or disorder, e.g., a subject having one or more risk factors known to be associated with the development or onset of the disease or disorder. Thus, the term "prophylaxis against HIV infection" refers to administering an anti-HIV therapeutic substance to a subject without detectable HIV infection. It should be understood that subjects for anti-HIV prophylactic treatment may be individuals at risk of infection with the HIV virus. It should also be understood that prophylaxis may not completely prevent the onset of a disease or disorder. In some cases, prophylaxis includes reducing the risk of developing a disease or disorder. The reduction of risk may not completely eliminate the risk of developing a disease or disorder.

[0154] As used herein, a "subject at risk" is an individual at risk of developing a disorder to be treated. A "subject at risk" may or may not have a detectable disease or disorder and may or may not have shown a detectable disease prior to treatment by the methods described herein. "At risk" means that the individual has one or more so-called risk factors, which are measurable parameters associated with the development of the disease or disorder and are known in the art. An individual having one or more of these risk factors has a higher likelihood of developing the disease or disorder than an individual without these risk factors. For example, individuals at risk of AIDS are those having HIV.

[0155] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit the desired biological or medical response, including an amount of a compound sufficient to effect such treatment of a disease when administered to an individual to treat the disease, or an amount effective to prevent infection or onset of a disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated. The effective amount can include a range of amounts. As understood in the art, the effective amount can be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic effect. The effective amount can be considered in the context of administering one or more therapeutic agents, and a single agent can be considered to be administered in an effective amount if the desired or beneficial result is achieved or enabled in combination with one or more other agents. Optionally, the appropriate dose of any co-administered compound can be reduced due to the combined action (e.g., additive or synergistic) of the compounds.

[0156] The compounds of the invention include their solvates, hydrates, tautomers, stereoisomers and salt forms.

[0157] The following compounds are also provided, wherein 1 to n hydrogen atoms attached to carbon atoms can be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can increase resistance to metabolism and can therefore be used to increase the half-life of the compound when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., 5(12):524-527 (1984). These compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0158] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. Substitution with positron-emitting isotopes (such as 11 C, 18 F, 15 O and 13 N) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotope-labeled compounds of formula (Ia) or (Ib) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the examples, as described below, using appropriate isotope-labeled reagents in place of the previously used unlabeled reagents.

[0159] As mentioned herein, darunavir is an HIV protease inhibitor having the following structure: And having the following IUPAC name: [(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate. Darunavir (DRV) is available under the trade name Sales

[0160] As mentioned herein, atazanavir is an HIV protease inhibitor having the following structure: And having the following IUPAC name: Methyl N-[(2S)-1-[2-[(2S,3S)-2-hydroxy-3-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoyl]amino]-4-phenylbutyl]-2-[(4-pyridin-2-ylphenyl)methyl]hydrazino]-3,3-dimethyl-1-oxobutan-2-yl]carbamate. Atazanavir (ATV) is sold under the trade name Sales

[0161] Compound

[0162] In certain embodiments, a compound of formula I is provided:

[0163]

[0164] Or a pharmaceutically acceptable salt thereof, wherein:

[0165] R 1 Is a 5- to 10-membered heterocycle having 1 to 5 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered heterocycle or 5- to 10-membered heteroaryl is optionally substituted with 1 to 5 R a Groups;

[0166] R 2 And R 3 Are each independently C 1-4 Alkyl, C 3-6 Cycloalkyl, O-R 2A C 1-2 Alkyl-O-R 2A N-(R 3A )2 or C 1-2 Alkyl-N-(R 3A )2,

[0167] Wherein each R 2A Is independently C 1-4 Alkyl, C 3-6 Cycloalkyl or a 4- to 10-membered heterocyclic group having 1 to 5 heteroatoms selected from N, O, and S,

[0168] Wherein each R 3A Is independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or COO(R e ),

[0169] and each C 3-6 cycloalkyl or 4- to 10-membered heterocyclic group is optionally substituted with 1 to 3 R f groups, where each R f is independently C 1-2 alkyl or halogen;

[0170] R 4 is hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;

[0171] R 7 is hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;

[0172] R 5 , R 6 , R 8 and R 9 are each independently hydrogen, halogen, C 1-2 alkyl, C 1-2 haloalkyl or C 3-6 cycloalkyl;

[0173] and where two or more of R 4 , R 5 and R 6 , or two or more of R 7 , R 8 and R 9 are optionally joined together to form one or more C 3-6 cycloalkyl groups, which are optionally substituted with 1 to 4 groups selected from halogen, C 1-2 alkyl and C 1-2 haloalkyl;

[0174] Each R 10 is independently halogen, cyano, C 1-4 alkoxy, C 1-6 alkyl or C 3-6 cycloalkyl;

[0175] n is 0 to 4;

[0176] Each R a is independently halogen, C 1-4 alkyl, C 1-4 alkyl having 1 to 2 groups selected from hydroxy and C1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, optionally substituted with R and having 1 to 5 heteroatoms selected from N, O, and S, or O-R a1 , 3B

[0177] wherein R 3B is optionally substituted with R a1 and is cycloalkyl or optionally substituted with R and having 1 to 5 heteroatoms selected from N, O, and S, a 4- to 10-membered heterocyclic group 3-6 a1

[0178] wherein each R a1 is independently C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl or a 4- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S;

[0179] A is ethynyl or a bond;

[0180] X 1 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 6- to 10-membered aryl or 5- to 10-membered heteroaryl is each optionally substituted with 1 to 4 R b groups;

[0181] X 2 is hydrogen or a 4- to 10-membered heterocyclic group having 1 to 5 heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclic group is optionally substituted with one R 11 and optionally substituted with 1 to 5 R b groups;

[0182] R 11 is C=O(R c ), CH2(R d ), S(O) 1-2 (C 1-4 alkyl), S(O) 1-2 C 3-6 cycloalkyl, a 4- to 10-membered heterocyclic group having 1 to 5 heteroatoms selected from N, O, and S, or a 5- to 9-membered heteroaryl having 1 to 5 heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclic group or 5- to 9-membered heteroaryl is each optionally substituted with 1 to 5 R b groups;

[0183] each R b is independently halogen, oxo, C​​​1-4 An alkyl group having 1 to 2 groups selected from the group consisting of hydroxy and C 1-4 alkoxy groups; 1-4 An alkyl group, C 1-4 A haloalkyl group, C 1-4 An alkoxy group or COO(R e ));

[0184] R c is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, N(R e ),2, C 3-6 cycloalkyl or a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S, wherein said C 3-6 cycloalkyl and said 4- to 6-membered heterocyclic group are optionally substituted with 1 to 5 R b groups;

[0185] R d is COO(R e ), N(R e ),2, C 3-6 cycloalkyl or a 4- to 6-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S, wherein said C 3-6 cycloalkyl and said 4- to 6-membered heterocyclic group are optionally substituted with 1 to 5 R b groups;

[0186] Each R 12 is C 1-2 alkyl, halogen, -OC 1-2 alkyl or cyano;

[0187] Each p is from 0 to 4;

[0188] And each R e is independently hydrogen or C 1-4 alkyl.

[0189] In certain embodiments, the compound of formula I is a compound of formula (Ia):

[0190]

[0191] Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X 1 and X 2 are as defined herein, and R10a and R 10b are independently halogen, cyano, C 1-4 alkoxy, C 1-6 alkyl or C 3-6 cycloalkyl.

[0192] In certain embodiments, the compound of formula I or formula (Ia) is a compound of formula (Ib)

[0193]

[0194] wherein: Z 1 and Z 2 are independently N or CH; m is 0 to 2, R 10a and R 10b are independently halogen, cyano, C 1-4 alkoxy, C 1-6 alkyl or C 3-6 cycloalkyl, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and X 2 are as defined herein.

[0195] In certain embodiments, the compound of formula I, (Ia) or (Ib) is a compound of formula (Ic):

[0196]

[0197] wherein Z 1 and Z 2 are independently N or CH, R 10a and R 10b are independently halogen, cyano, C 1-4 alkoxy, C 1-6 alkyl or C 3-6 cycloalkyl, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined herein.

[0198] In certain embodiments, the compound of formula I or (Ia) is a compound of formula (Id):

[0199]

[0200] wherein R 10a and R 10b are independently halogen, cyano, C 1-4 alkoxy, C 1-6 alkyl or C 3-6 cycloalkyl, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X 1 and X 2 are as defined herein.

[0201] In certain embodiments, the compound of formula I or (Ia) is a compound of formula (Ie):

[0202]

[0203] wherein R 1 , R a , R 11 , X 1 and X 2 are as defined herein.

[0204] In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 4 and R 7 may be the same or different. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 4 is hydrogen, C 1-4 alkyl or C 1-4 haloalkyl. In certain embodiments, R 4 is C 1-4 haloalkyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 4 is CF3. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 7 is hydrogen, C 1-4 alkyl or C 1-4 haloalkyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 7 is C 1-4 haloalkyl. In certain embodiments, R 7is CF3. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 4 and R 7 are CF3 or methyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 5 , R 6 R 8 and R 9 may be the same or different. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 5 R 6 R 8 and R 9 are each independently hydrogen, halogen, C 1-2 alkyl, C 1-2 haloalkyl or C 3-6 cycloalkyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 5 R 6 R 8 and R 9 are hydrogen, methyl or fluorine. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 5 and R 6 are C 1-2 alkyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 5 and R 6 are methyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 8 and R 9 are C 1-2 alkyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 8 and R 9 are methyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), two or more of R 4 , R 5 and R 6 , or two or more of R 7 , R 8 and R 9 may be joined together to form one or more C 3-6 cycloalkyl groups, which are optionally substituted with hydrogen.

[0205] In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R 1 is a 5- to 6-membered heterocycle having 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, wherein the 5- to 6-membered heterocycle or 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 R a groups. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R 1 is a 5- to 6-membered heterocycle having 1 to 3 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 3 R a groups. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R 1 is:

[0206] In certain embodiments, R 1 is or In certain embodiments, R 1 is:

[0207] In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R a is independently C 1-4 alkyl, C 1-4 alkyl having 1 to 2 groups selected from hydroxy and C 1-4 alkoxy, C 1-4 haloalkyl, or a 4- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, optionally substituted with R a1 . In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R a is independently C 1-4 alkyl, C 1-4 alkyl having 1 to 2 groups selected from hydroxy and C 1-4 alkoxy, C 1-4 haloalkyl, furanyl, oxetanyl or 3,8-diazabicyclo[3.2.1]octyl, optionally substituted with R a1 . In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R a is independently C 1-4 alkyl, C 1-4 alkyl having 1 to 2 groups selected from hydroxy and C 1-4 alkoxy or C1-4 Halogenated alkyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R a is:

[0208]

[0209] In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R a is C 1-4 Halogenated alkyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R a is:

[0210] In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R a may be substituted by R a1 In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R a is substituted by one R a1 group. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R a1 is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 halogenated alkyl or a 4- to 8-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), the 4- to 8-membered heterocyclic group contains 1 to 2 nitrogen heteroatoms or 1 to 2 oxygen atoms.

[0211] In certain embodiments of the compounds of formula (I), (Ia) or (Ie), X 1 is a 6-membered aryl or a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, wherein the 6-membered aryl or 5- to 6-membered heteroaryl is each optionally substituted by 1 to 4 R b groups. In certain embodiments of the compounds of formula (I), (Ia) or (Ie), X 1 is pyrimidine or pyridine, which is optionally substituted by 1 to 4 R b groups. In certain embodiments of the compounds of formula (I), (Ia) or (Ie), X 1 is pyrimidine or pyridine. In certain embodiments of the compounds of formula (I), (Ia) or (Ie), X 1 is:

[0212] In certain embodiments of the compound of formula (I), (Ia) or (Ie), X 1 is In certain embodiments of the compound of formula (I), (Ia) or (Ie), X 1 is

[0213] In certain embodiments of the compound of formula (I), (Ia), (Ib), (Id) or (Ie), X 2 is a 4- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, and is optionally substituted with one R 11 substituent and optionally substituted with 1 to 5 R b groups. In certain embodiments, X 2 may be substituted with R 11 or R b substituent. In certain embodiments of the compound of formula (I), (Ia), (Ib), (Id) or (Ie), X 2 is:

[0214]

[0215] In certain embodiments of the compound of formula (I), (Ia), (Ib), (Id) or (Ie), X 2 is: In certain embodiments of the compound of formula (I), (Ia), (Ib), (Id) or (Ie), X 2 is:

[0216] In certain embodiments of the compound of formula (I), (Ia), (Ib), (Id) or (Ie), X 2 is wherein:

[0217] a) R P1 , R P2 , R P3 and R P4 are each hydrogen;

[0218] b) R P1 and R P3 together form a –CH2– or –CH2CH2– group, and R P2 and R P4 are each hydrogen;

[0219] c) R P2 and R P4 together form a –CH2– or –CH2CH2– group, and R P1 and RP3 each is hydrogen;

[0220] d) R P1 and R P4 together form a –CH2– group, and R P2 and R P3 each is hydrogen; or

[0221] e) R P2 and R P3 together form a –CH2– group, and R P1 and R P4 each is hydrogen.

[0222] In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Id) or (Ie), X 2 is wherein:

[0223] R P1 and R P3 together form a –CH2– or –CH2CH2– group, and R P2 and R P4 each is hydrogen; or

[0224] R P2 and R P4 together form a –CH2– or –CH2CH2– group, and R P1 and R P3 each is hydrogen.

[0225] In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), X 2 is optionally substituted by R 11 . In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R 11 is a 4- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R 11 is a 4- to 6-membered heterocyclic group having 1 O. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R 11 is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie), R 11 is oxetan-3-yl, tetrahydrofuran-3-yl or tetrahydropyran-4-yl.

[0226] In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 2 and R 3 may be the same or different. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 2 and R 3 are each independently C 1-4 alkyl, C 3-6 cycloalkyl or O-R 2A , where R 2A is C 1-4 alkyl, C 3-6 cycloalkyl, or a 4- to 10-membered heterocyclic group having 1 to 5 heteroatoms selected from N, O, and S. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 2 and R 3 are each independently In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), R 2 and R 3 are each methoxy.

[0227] In certain embodiments of the compounds of formula (I), when n is greater than 1, each R 10 may be the same or different. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), n = 0, 1 or 2. In certain embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), each R 10 is halogen. In certain embodiments, each R 10 is chlorine or fluorine. In certain embodiments of the compounds of formula (Ia), (Ib), (Ic) or (Id), R 10a and R 10b may be the same or different. In certain embodiments of the compounds of formula (Ia), (Ib), (Ic) or (Id), R 10a and R 10b are each halogen. In certain compounds of formula (Ia), (Ib), (Ic) or (Id), R 10a and R 10b are each chlorine or fluorine.

[0228] In certain embodiments of the compounds of formula I, A is ethynyl. In certain embodiments of the compounds of formula I, A is a bond.

[0229] In certain embodiments, whenever present, X 1 and X 2 may each be substituted by one or more R bGroup substitution. In certain embodiments, each R b is independently a halogen, oxo C 1-4 alkyl, C 1-4 alkyl having 1 to 2 groups selected from hydroxy and C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkoxy or COO(R e ). In certain embodiments, each R b is independently oxo or halogen.

[0230] In certain embodiments of the compound of formula I, each R 12 is C 1-2 alkyl, halogen, -OC 1-2 alkyl or cyano. In certain embodiments of the compound of formula I, R 12 is fluorine, chlorine or methyl.

[0231] In certain embodiments of the compound of formula (Ib) or (Ic), one of Z 1 and Z 2 is N and the other is CH. In certain embodiments of the compound of formula (Ib) or (Ic), both Z 1 and Z 2 are N.

[0232] As disclosed above, any definitions of the provided variables (e.g., A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 10a , R 10b , Z 1 , Z 2 , X 1 and X 2 ) can be combined and grouped with other variables, whether or not specifically described together.

[0233] In certain embodiments of the compound of formula (Ia), R 1 is R a is C 1-4 haloalkyl; X 1 is pyrimidine or pyridine, R 2 and R 3 are each methoxy, R 4 is CH3 or CF3, R7 is CH3 or CF3, R 5 , R 6 , R 8 and R 9 each is methyl, X 2 is: R 10a and R 10b each is halogen; and R 11 is a 4- to 6-membered heterocycle having one oxygen.

[0234] In certain embodiments of the compound of formula (Ib), R 1 is R a is C 1-4 haloalkyl; m is 0, Z 1 and Z 2 are independently N or CH, R 2 and R 3 each is methoxy, R 4 is CH3 or CF3, R 7 is CH3 or CF3, R 5 , R 6 , R 8 and R 9 each is methyl; X 2 is: R 10a and R 10b each is halogen; and R 11 is a 4- to 6-membered heterocycle having one oxygen.

[0235] In certain embodiments of the compound of formula (Ic), R 1 is R a is C 1-4 haloalkyl; Z 1 and Z 2 are independently N or CH, R 2 and R 3 each is methoxy, R 4 is CH3 or CF3, R 7 is CH3 or CF3, R 5 , R 6 , R 8 and R 9 each is methyl; R 10a and R 10b each is halogen; and R 11 is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl. In certain embodiments of the compound of formula (Id), R 1 is R a is –CHF2; X1 is pyrimidine or pyridine, R 2 and R 3 are each methoxy, R 4 is CH3 or CF3, R 7 is CH3 or CF3, R 5 , R 6 , R 8 and R 9 are each methyl, X 2 is: and R 10a and R 10b are each halogen, and R 11 is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

[0236] In certain embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[0237] In certain embodiments, the compound is a compound of any one of Examples 1-245, or a pharmaceutically acceptable salt thereof.

[0238] In certain embodiments, the compound is

[0239] or a pharmaceutically acceptable salt thereof.

[0240] In certain embodiments, the compound is

[0241] or a pharmaceutically acceptable salt thereof.

[0242] In certain embodiments, the compound is

[0243] or a pharmaceutically acceptable salt thereof.

[0244] In certain embodiments, the compound is

[0245] or a pharmaceutically acceptable salt thereof.

[0246] In certain embodiments, the compound is

[0247] or a pharmaceutically acceptable salt thereof.

[0248] In certain embodiments, the compound is

[0249] or a pharmaceutically acceptable salt thereof.

[0250] In certain embodiments, the compound is

[0251] or a pharmaceutically acceptable salt thereof.

[0252] In certain embodiments, the compound is

[0253] or a pharmaceutically acceptable salt thereof.

[0254] In certain embodiments, the compound is

[0255] or a pharmaceutically acceptable salt thereof.

[0256] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0257] In certain embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0258] Treatment Method

[0259] The pharmaceutical composition of the compound of formula (I) (including the compounds of formula (Ia)-(Ie)) can be administered in a single dose or multiple doses by any acceptable mode of administration of a medicament having a similar utility, such as those described in the patents and patent applications incorporated by reference herein, including rectal, oral, intranasal, and transdermal routes, such as by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or by means of an impregnated or coated device such as a stent, or a cylindrical polymer inserted into an artery.

[0260] In one aspect, the compounds described herein can be administered orally. Oral administration can be carried out, for example, by capsules or enteric-coated tablets. When preparing a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, it is generally diluted with an excipient and / or encapsulated in a carrier which can be in the form of a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as described above) and serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0261] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may also include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl paraben and propyl paraben; sweetening agents; and flavoring agents.

[0262] Compositions comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof can be formulated to provide rapid, sustained, or delayed release of the active ingredient following administration to a subject by methods known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems that comprise polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in a controlled amount. The construction and use of transdermal patches for delivering medicaments are well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of the medicament.

[0263] In some embodiments, the compositions can be formulated as unit dosage forms. The term “unit dosage form” refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect, together with the suitable pharmaceutical excipients (e.g., tablets, capsules, ampoules). The compounds are generally administered in a pharmaceutically effective amount. In some embodiments, for oral administration, each dosage unit contains from about 10 mg to about 1000 mg of the compounds described herein, such as from about 50 mg to about 500 mg, such as about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In other embodiments, for parenteral administration, each dosage unit contains from 0.1 to 700 mg of the compounds described herein. However, it will be understood that the actual amount of the compound administered is usually determined by the physician, in view of the relevant circumstances, including the condition to be treated, the route of administration actually employed, the compound actually administered and its dosage, the age, weight, and response of the individual subject, and the severity of the subject's symptoms.

[0264] In certain embodiments, the dosage level can be from 0.1 mg to 100 mg per kilogram of body weight per day, such as from about 1 mg to about 50 mg per kilogram of body weight, such as from about 5 mg to about 30 mg per kilogram of body weight. In certain cases, such dosage levels can be used to treat the above-mentioned conditions. In other embodiments, the dosage level can be from about 10 mg to about 2000 mg per subject per day. The amount of the active ingredient that can be combined with the vehicle to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The dosage unit form can contain from 1 mg to 1000 mg of the active ingredient.

[0265] The compounds or their pharmaceutically acceptable salts disclosed herein can be administered to a subject for a desired period or duration according to an effective dosing regimen, such as for at least about one day, at least about one week, at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule. In one variation, the compound is used on a monthly schedule. In one variation, the compound is administered every two months. In one variation, the compound is administered every three months. In one variation, the compound is administered every four months. In one variation, the compound is administered every five months. In one variation, the compound is administered every 6 months.

[0266] Based on the judgment of the attending physician, the dosage or dosing frequency of the compounds or their pharmaceutically acceptable salts disclosed herein can be adjusted during the course of treatment. The compound can be administered to a subject (such as a human) in an effective amount. In certain embodiments, the compound is used once a day.

[0267] To prepare a solid composition such as a tablet, the primary active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition, which contains a homogeneous mixture of the compound of formula (I) or its pharmaceutically acceptable salt. When these preformulation compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0268] The tablets or pills of the compounds described herein can be coated or otherwise mixed to provide a dosage form that has the advantage of extended action or protects the stomach from acidic conditions. For example, a tablet or pill can contain an internal dosage and an external dosage component, the latter being in an encapsulated form over the former. These two components can be separated by an enteric layer, which is used to resist disintegration in the stomach and allow the internal component to enter the duodenum intact or be released in a delayed manner. Such enteric layers or coatings can use a variety of materials, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0269] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) will include one or more excipients. The excipients should be compatible with the other components of the formulation and physiologically innocuous to its recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and can be found, for example, in Handbook of Pharmaceutical Excipients (edited by Rowe, Sheskey & Quinn), 6th edition, 2009.

[0270] In some embodiments, the compounds or pharmaceutically acceptable salts thereof described herein can be administered by syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the compounds or pharmaceutically acceptable salts thereof described herein.

[0271] In some embodiments, the compounds or pharmaceutically acceptable salts thereof described herein can be co-administered with an autoinjector comprising a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the compounds or pharmaceutically acceptable salts thereof described herein.

[0272] In certain embodiments, a method of treating or preventing human immunodeficiency virus (HIV) infection is provided, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof disclosed herein. In certain embodiments, a method of treating human immunodeficiency virus (HIV) infection is provided, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof disclosed herein. In certain embodiments, the method comprises co-administering the compound or a pharmaceutically acceptable salt thereof disclosed herein with one, two, three or four additional therapeutic agents. In certain embodiments, the subject is at risk of HIV virus infection, such as a subject having one or more risk factors known to be associated with HIV virus infection. In certain embodiments, the subject may not have previously received antiviral treatment (treatment-naive). In certain embodiments, the subject may have previously received antiviral treatment (treatment-experienced). In certain embodiments, the subject may have previously received antiviral treatment and developed resistance to the previously received antiviral treatment.

[0273] In certain embodiments, a method of treating or preventing human immunodeficiency virus (HIV) infection is provided, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds targeting the HIV capsid, immunotherapy-based agents, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 virion infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic cell ICAM-3-grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, or any combination thereof. In certain embodiments, the one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents are selected from HIV protease inhibitor compounds, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combination thereof.In certain embodiments, the one or more additional therapeutic agents do not include a pharmacokinetic enhancer.

[0274] In certain embodiments, a method is disclosed for inhibiting the replication of the HIV virus, treating AIDS, or delaying the onset of AIDS in a subject (e.g., a human), which comprises administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0275] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is disclosed for use in the medical treatment of HIV infection (e.g., HIV-1) or the replication of the HIV virus (e.g., HIV-1) or AIDS or delaying the onset of AIDS in a subject (e.g., a human).

[0276] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is disclosed for use in the manufacture of a medicament for treating HIV infection or the replication of the HIV virus or AIDS or delaying the onset of AIDS in a subject (e.g., a human). One embodiment relates to a compound disclosed herein or a pharmaceutically acceptable salt thereof for prophylactic or therapeutic treatment of HIV infection or AIDS, or for therapeutic treatment or delaying the onset of AIDS.

[0277] In certain embodiments, the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for HIV infection in a subject (e.g., a human) is disclosed. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof for prophylactic or therapeutic treatment of HIV infection is disclosed.

[0278] In certain embodiments, in the method of use, the administration is to a subject (e.g., a human) in need of treatment. In certain embodiments, in the method of use, the administration is to a subject (e.g., a human) at risk of developing AIDS.

[0279] A compound disclosed herein or a pharmaceutically acceptable salt thereof for use in treatment is provided. In one embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is used in a method for treating HIV infection or the replication of the HIV virus or AIDS or delaying the onset of AIDS in a subject (e.g., a human).

[0280] Provided is a compound disclosed herein or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HIV infection in a subject in need thereof. In certain embodiments, provided is a compound disclosed herein or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a subject in need thereof. In certain embodiments, the subject in need thereof is a human who has been infected with HIV. In certain embodiments, the subject in need thereof is a human who has been infected with HIV but has not developed into AIDS. In certain embodiments, the subject in need thereof is a subject at risk of developing into AIDS. In certain embodiments, the subject in need thereof is a human who has been infected with HIV and has developed into AIDS.

[0281] In one embodiment, there is provided a combination of a compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents as described herein for use in a method of treating or preventing HIV infection in a subject in need thereof. In one embodiment, the additional therapeutic agent is selected from: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 virion infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines or any combination thereof. In certain embodiments, the additional therapeutic agent is selected from HIV protease inhibitory compounds, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combination thereof.

[0282] In one embodiment, there is provided a combination of a compound disclosed herein or a pharmaceutically acceptable salt thereof with a first additional therapeutic agent selected from tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine, for use in a method of treating or preventing HIV infection in a subject in need thereof. In a particular embodiment, there is provided a combination of a compound disclosed herein or a pharmaceutically acceptable salt thereof with a first additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine, for use in a method of treating or preventing HIV infection in a subject in need thereof.

[0283] In a particular embodiment, there is provided a compound disclosed herein or a pharmaceutically acceptable salt thereof for preventing HIV infection and / or preventing the virus from establishing a permanent infection and / or preventing the appearance of symptoms of the disease and / or preventing the virus from reaching a detectable level in the blood when an individual is exposed to the virus, e.g., for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Accordingly, in certain embodiments, there is provided a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2). For example, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes co-administering a compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more additional therapeutic agents. In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes administering a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0284] In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes administering a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with safer sexual behavior. In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) includes administering to an individual at risk of acquiring HIV. Examples of individuals at high risk of acquiring HIV include, but are not limited to, individuals at risk of sexually transmitted HIV.

[0285] In certain embodiments, the reduction in the risk of acquiring HIV is at least about 40%, 50%, 60%, 70%, 80%, 90% or 95%. In certain embodiments, the reduction in the risk of acquiring HIV is at least about 75%. In certain embodiments, the reduction in the risk of acquiring HIV is about 80%, 85% or 90%.

[0286] In another embodiment, there is disclosed the use of a compound or a pharmaceutically acceptable salt thereof disclosed herein in the manufacture of a medicament for the treatment of HIV infection in a human being who has or is at risk of having an HIV infection.

[0287] There is also disclosed herein a compound or a pharmaceutically acceptable salt thereof for the therapeutic treatment or delaying the onset of AIDS.

[0288] There is also disclosed herein a compound or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of HIV infection.

[0289] In certain embodiments, a compound or a pharmaceutically acceptable salt thereof disclosed herein can be used as a research tool (e.g., for studying the inhibition of HIV reverse transcriptase in an individual or in vitro).

[0290] There is provided a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a suitable package. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and instructions for use of the compound in the treatment of a disease or disorder described herein.

[0291] There is provided an article comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in a suitable container. The container can be a vial, a canister, an ampoule, a prefilled syringe and an intravenous bag.

[0292] Administration of HIV combination therapy

[0293] In certain embodiments, a compound disclosed herein is administered in combination with one or more additional therapeutic agents. Co - administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient. When administered sequentially, the combination can be administered in two or more administrations.

[0294] Co - administration involves administering a unit dose of the compounds disclosed herein before or after administering a unit dose of one or more additional therapeutic agents. For example, the compounds disclosed herein can be administered within seconds, minutes, or hours of administering one or more additional therapeutic agents. In some embodiments, a unit dose of the compounds disclosed herein is administered first, and then a unit dose of one or more additional therapeutic agents is administered within seconds or minutes. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, and then a unit dose of the compounds disclosed herein is administered within seconds or minutes. In other embodiments, a unit dose of the compounds disclosed herein is administered first, and then a unit dose of one or more additional therapeutic agents is administered after a period of hours (e.g., 1 - 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, and then a unit dose of the compounds disclosed herein is administered after a period of hours (e.g., 1 - 12 hours).

[0295] In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, such as a solid dosage form for oral administration.

[0296] In certain embodiments, the compound of formula (I) is formulated into a tablet, which may optionally contain one or more other compounds for the treatment of HIV. In certain embodiments, the tablet can contain additional active ingredients for the treatment of HIV, such as an HIV protease inhibitor, a non - nucleoside or non - nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, an HIV non - catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0297] In some embodiments, the compound of formula (I) is formulated into a tablet, which may optionally contain one or more other compounds for the treatment of HIV. In certain embodiments, the tablet can contain additional active ingredients for the treatment of HIV, such as a compound targeting the HIV capsid, an HIV protease inhibitor, a non - nucleoside or non - nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, an HIV non - catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0298] In some embodiments, the compounds targeting the HIV capsid are selected from:

[0299] or a pharmaceutically acceptable salt thereof.

[0300] In certain embodiments, such tablets are suitable for once - daily dosing.

[0301] HIV combination therapy

[0302] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0303] In some embodiments, the additional therapeutic agent is selected from: immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALEN), and cell therapies, such as chimeric antigen receptor T cells (CAR-T) (e.g., (axicabtagene ciloleucel)) and engineered T cell receptors (TCR-T).

[0304] In some embodiments, the additional therapeutic agent is selected from: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0305] HIV combination drugs

[0306] Examples of combination drugs include (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; (zidovudine and lamivudine; AZT+3TC); ( (abacavir sulfate and lamivudine; ABC+3TC); ( (lopinavir and ritonavir); (dolutegravir, abacavir, and lamivudine); (Abacavir Sulfate, Zidovudine and Lamivudine; ABC+AZT+3TC); Atazanavir and Cobicistat; Atazanavir Sulfate and Cobicistat; Atazanavir Sulfate and Ritonavir; Darunavir and Cobicistat; Dolutegravir and Rilpivirine; Dolutegravir and Rilpivirine Hydrochloride; Dolutegravir, Abacavir Sulfate and Lamivudine; Lamivudine, Nevirapine and Zidovudine; Raltegravir and Lamivudine; Doravirine, Lamivudine and Tenofovir Disoproxil Fumarate; Doravirine, Lamivudine and Tenofovir Disoproxil; Dolutegravir + Lamivudine; Lamivudine + Abacavir + Zidovudine; Lamivudine + Abacavir, Lamivudine + Tenofovir Disoproxil Fumarate, Lamivudine + Zidovudine + Nevirapine, Lopinavir + Ritonavir, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lopinavir + Ritonavir + Zidovudine + Lamivudine, Tenofovir + Lamivudine; and Tenofovir Disoproxil Fumarate + Emtricitabine + Rilpivirine Hydrochloride, Lopinavir, Ritonavir, Zidovudine and Lamivudine; Vacc-4x and Romidepsin; and APH-0812.

[0307] Other HIV drugs

[0308] Examples of other drugs for the treatment of HIV include acetylmethadol, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

[0309] HIV protease inhibitors

[0310] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, and TMC-310911.

[0311] HIV reverse transcriptase inhibitors

[0312] Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, and VM-1500.

[0313] In some embodiments, examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, PC-1005, and VM-1500.

[0314] Examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fisalvudinetidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil lactobionate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, and KP-1461.

[0315] HIV integrase inhibitors

[0316] Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, phenethyl caffeate, phenethyl caffeate derivatives, tyrosine phosphorylation inhibitors, tyrosine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, and cabotegravir.

[0317] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442.

[0318] HIV entry inhibitors

[0319] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

[0320] Examples of CCR5 inhibitors include apravir, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), nifivir (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0321] Examples of gp41 inhibitors include ibalizumab, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0322] Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

[0323] Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicines, fosamprenavir tromethamine, IQP-0831, and BMS-663068.

[0324] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0325] HIV maturation inhibitors

[0326] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

[0327] Latency reversing agents

[0328] Examples of latency reversing agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as bortezomib (velcade), protein kinase C (PKC) activators, BET bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (succinylanilide hydroxamic acid, or succinyl, aniline, and hydroxamic acid), IL-15, JQ1, disulfiram, amphotericin B, ubiquitin inhibitors such as lagzola analogs, and GSK-343.

[0329] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0330] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactone.

[0331] Capsid inhibitors

[0332] Examples of capsid inhibitors include capsid polymerization inhibitors or compounds that disrupt the capsid, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series;

[0333] In some embodiments, examples of capsid inhibitors include:

[0334] or a pharmaceutically acceptable salt thereof.

[0335] In some embodiments, the capsid inhibitor is selected from:

[0336] or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, the capsid inhibitor is:

[0338] or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the capsid inhibitor is:

[0340] or a pharmaceutically acceptable salt thereof.

[0341] Immune-based therapies

[0342] Examples of immune-based therapies include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15 agonists; DermaVir; interleukin-7; quinine (hydroxychloroquine); interleukin (aldesleukin, IL-2); interferon α; interferon α-2b; interferon α-n3; pegylated interferon α; interferon γ; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, the polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, normferon, pegylated interferon α-2a, pegylated interferon α-2b, recombinant interleukin-15, RPI-MN, GS-9620, and IR-103.

[0343] In some embodiments, examples of immune-based therapies include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15 agonists; DermaVir; interleukin-7; quinine (hydroxychloroquine); interleukin (aldesleukin, IL-2); interferon α; interferon α-2b; interferon α-n3; pegylated interferon α; interferon γ; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, the polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, normferon, pegylated interferon α-2a, pegylated interferon α-2b, recombinant interleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators, NOD2 modulators, and IR-103.

[0344] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0345] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.

[0346] α-4 / β-7 antagonists

[0347] Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, ablumapalivizumab, etrolizumab, carotegrast methyl, and vedolizumab.

[0348] HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

[0349] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include Fab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41, antibody-recruiting molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant monoclonal antibodies (PGT-121), ibalizumab, Immuglo, MB-66.

[0350] Examples of those targeting HIV in this manner include bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5 + C2G12 + C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523, VRC-HIVMAB080-00-AB, MGD-014, and VRC07.

[0351] In some embodiments, examples of those targeting HIV in this manner include bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5 + C2G12 + C4E10, 8ANC195, 3-BNC-117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32, 7B2, 10E8, 10E8v4, CAP256-VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, MGD-014, and VRC07. An example of an HIV bispecific antibody is MGD014.

[0352] Pharmacokinetic enhancer

[0353] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0354] Additional therapeutic agents

[0355] Examples of additional therapeutic agents include compounds disclosed in the following: WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences)), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco Inc.), US2014 / 0221380 (Japan Tobacco Inc.), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim).

[0356] HIV vaccine

[0357] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[δ]V2.TV1+MF-59, rVSVIN HIV-1gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccines, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines such as pseudovirus particle vaccines, CombiVICHvac, LFn-p24B / C fusion vaccines, GTU-based DNA vaccines, HIVgag / pol / nef / env DNA vaccines, anti-TAT HIV vaccines, conjugated polypeptide vaccines, dendritic cell vaccines, gag-based DNA vaccines, GI-2010, gp41HIV-1 vaccines, HIV vaccines (PIKA adjuvant), Ii-key / MHC class II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multi-branched Env vaccines, MVA vaccines, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccines, recombinant peptide vaccines (HIV infection), NCI, rgp160HIV vaccines, RNActive HIV vaccines, SCB-703, Tat Oyi vaccines, TBC-M4, therapeutic HIV vaccines, UBI HIV gp120, Vacc-4x + romidepsin, variant gp120 polypeptide vaccines, rAd5gag-pol env A / B / C vaccines.

[0358] In some embodiments, examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAXB / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[δ]V2.TV1+MF-59, rVSVIN HIV-1gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccines, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines such as pseudovirus particle vaccines, CombiVICHvac, LFn-p24B / C fusion vaccines, GTU-based DNA vaccines, HIV gag / pol / nef / env DNA vaccines, anti-TAT HIV vaccines, conjugated polypeptide vaccines, dendritic cell vaccines, gag-based DNA vaccines, GI-2010, gp41HIV-1 vaccines, HIV vaccines (PIKA adjuvant), Ii-key / MHC class II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multi-branched Env vaccines, MVA vaccines, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccines, recombinant peptide vaccines (HIV infection), NCI, rgp160HIV vaccines, RNActive HIV vaccines, SCB-703, Tat Oyi vaccines, TBC-M4, therapeutic HIV vaccines, UBI HIV gp120, Vacc-4x + romidepsin, variant gp120 polypeptide vaccines, rAd5gag-pol env A / B / C vaccines, DNA.HTI, and MVA.HTI.

[0359] HIV combination therapies

[0360] In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with one, two, three, four or more additional therapeutic agents selected from the following: (efavirenz, tenofovir disoproxil fumarate and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (Dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ( lopinavir and ritonavir); (zidovudine and lamivudine; AZT + 3TC); ( abacavir sulfate and lamivudine; ABC + 3TC); (abacavir sulfate, zidovudine, and lamivudine; ABC + AZT + 3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0361] Those skilled in the art will understand that the additional therapeutic agents listed above may be included in more than one of the categories listed above. The specific categories are not intended to limit the functions of the compounds listed in those categories.

[0362] In one specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with nucleoside or nucleotide inhibitors of HIV reverse transcriptase and non-nucleoside inhibitors of HIV reverse transcriptase. In another specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with nucleoside or nucleotide inhibitors of HIV reverse transcriptase and compounds that inhibit HIV protease. In additional embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with nucleoside or nucleotide inhibitors of HIV reverse transcriptase, non-nucleoside inhibitors of HIV reverse transcriptase, and pharmacokinetic enhancers. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with at least one nucleoside inhibitor of HIV reverse transcriptase, integrase inhibitors, and pharmacokinetic enhancers. In another embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

[0363] In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0364] In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0365] In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from emtricitabine and lamivudine.

[0366] In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with a first additional therapeutic agent selected from tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0367] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with a capsid inhibitor (e.g., a capsid polymerization inhibitor and / or a capsid disrupting compound).

[0368] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with a capsid inhibitor (from about 10 to about 1000 mg) selected from:

[0369] or a pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with a capsid inhibitor selected from:

[0371]

[0372] or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with:

[0374] or a pharmaceutically acceptable salt thereof.

[0375] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with the following:

[0376] or a pharmaceutically acceptable salt thereof.

[0377] A compound disclosed herein (e.g., any compound of formula (I)) can be combined with one or more additional therapeutic agents at any dose of the compound of formula (I) (e.g., 1 mg to 1000 mg of the compound).

[0378] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 5 - 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, or any salt or solvate of tenofovir alafenamide. In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 5 - 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 5 - 10, 5 - 15, 5 - 20, 5 - 25, 25 - 30, 20 - 30, 15 - 30 or 10 - 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of formula (I)) can be combined with the agents provided herein at any dose of the compound (e.g., 1 mg to 1000 mg of the compound) as if each dose combination was specifically and individually listed.

[0379] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 200 - 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 200 - 250, 200 - 300, 200 - 350, 250 - 350, 250 - 400, 350 - 400, 300 - 400, or 250 - 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of formula (I)) can be combined with the agents provided herein at any dose of the compound (e.g., 1 mg to 1000 mg of the compound), as if each dose combination were specifically and individually listed.

[0380] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HIV nucleoside or nucleotide inhibitor and an integrase inhibitor. In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with GS - 9131 and bictegravir.

[0381] In one embodiment, a kit is provided that comprises a combination of a compound disclosed herein or a pharmaceutically acceptable salt thereof and one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0382] Contraceptive combination therapy

[0383] Therapeutic agents for contraception include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levomefolate, levonorgestrel, linestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, noretynodrel, norethisterone, norethisterone acetate, norgestimate, ormeloxifene, segestersone acetate, ulipristal acetate, and any combination thereof.

[0384] Gene therapy and cell therapy

[0385] Gene therapies and cell therapies include genetic modification to silence genes; genetic methods to directly kill infected cells; immunocyte infusion aimed at replacing most of the patient's own immune system to enhance the immune response against infected cells, or activating the patient's own immune system to kill infected cells, or discovering and killing infected cells; genetic methods to alter cell activity to further alter the endogenous immune response against infection.

[0386] Examples of dendritic cell therapies include AGS-004.

[0387] Gene editing agents

[0388] The genome editing system is selected from: CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, homing endonuclease system, and meganuclease system.

[0389] Examples of HIV-targeted CRISPR / Cas9 systems include EBT101.

[0390] CAR-T cell therapy

[0391] A population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen-binding domain. The HIV antigen comprises an HIV envelope protein or a portion thereof, gp120 or a portion thereof, the CD4 binding site on gp120, the CD4-induced binding site on gp120, the N-glycan on gp120, the V2 of gp120, the membrane-proximal region of gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof.

[0392] Examples of HIV CAR-T include VC-CAR-T.

[0393] TCR-T cell therapy

[0394] TCR-T cells are engineered to target HIV-derived peptides present on the surface of virus-infected cells.

[0395] Certain embodiments of the methods disclosed herein exclude the administration of pharmacokinetic enhancers. For example, in certain methods disclosed herein, during treatment with a compound disclosed herein or a pharmaceutically acceptable salt thereof, a pharmacokinetic enhancer, such as cobicistat or ritonavir, is not administered to the subject. Therefore, in certain embodiments, a method for treating or preventing human immunodeficiency virus (HIV) infection is provided, comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the treatment does not include the administration of a pharmacokinetic enhancer. In certain embodiments, a method for treating or preventing human immunodeficiency virus (HIV) infection is provided, comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need thereof once a day, wherein the treatment does not include the administration of a pharmacokinetic enhancer.

[0396] The present disclosure also provides all P, S, A and I intermediates described in the Examples section below.

[0397] Example

[0398] Methods for preparing the novel compounds described herein will be apparent to those skilled in the art, for example, suitable methods are described in the following reaction schemes and examples.

[0399] Sections 1.1-1.8 provide exemplary synthetic schemes for assembling compounds of Formula I. Sections 2.1-2.4 show the preparation of Intermediate I, Intermediate P, Intermediate S, and Intermediate A as used herein. Section 3 provides exemplary syntheses and compounds. Section 4 shows biological activity.

[0400] 1. General Scheme

[0401] Scheme 1.1

[0402] Scheme 1.1 shows the general synthesis of compounds within the scope of Formula I, starting with a substituted benzyl

[0403]

[0404] The aldehyde (intermediate P) is firstly reacted with the reductive amination of compound 1.1a. The reductive amination can be accomplished, for example, with a cyanoborohydride reagent such as sodium cyanoborohydride. This is followed by a metal catalyzed coupling such as a Sonogashira or Suzuki coupling. Compound 1.1b is reacted with the alkynyl intermediate S a Sonogashira coupling of 1,2-dihydro-1,4-dihydro-2-nitropropene gives the compound of formula I.

[0405] Examples 1-130, 219, and 224-245 were prepared by this general strategy (by reductive amination of the appropriate intermediate P with the corresponding organic halide peptide intermediate I, followed by Sonogashira coupling with the appropriate intermediate S). Example 1 provides exemplary reaction conditions and reagents suitable for preparing compounds of formula I according to Scheme 1.1.

[0406] Scheme 1.2

[0407]

[0408] Scheme 1.2 shows the general synthesis of compounds within the scope of formula I, using reductive amination of the protected hydrazinoiodophenylbutanol compound 1.2a. Exemplary protecting groups (PG) for compound 1.2a include the tert-butylcarbonyl (BOC) protecting group and the fluorenylmethyloxycarbonyl (FMOC). Reductive amination of compound 1.2a with the substituted benzaldehyde intermediate P, followed by removal of the protecting group, gives compound 1.2b. As a non-limiting example, reductive amination can be accomplished with sodium cyanoborohydride. Compound 1.2b is coupled with the amino acid intermediate A m using HATU to give compound 1.2c. Sonogashira coupling of compound 1.2c with the alkyne intermediate S a gives the compound of formula I.

[0409] Examples 133-180 and 220 were prepared by this general strategy (reductive amination of the appropriate P with hydrazinoiodophenylbutanol, then HATU coupling with A m , followed by Sonogashira coupling with the alkynyl intermediate S a ). Example 133 provides exemplary reaction conditions and reagents suitable for preparing compounds of formula I according to Scheme 1.2.

[0410] Scheme 1.3

[0411]

[0412] Scheme 1.3 shows the general synthesis of compounds within the scope of formula I, starting with reductive amination of the protected organic halide 1.3a with the benzaldehyde intermediate P and removal of Boc to give compound 1.3b. As a non-limiting example, reductive amination can be accomplished with sodium cyanoborohydride. As a non-limiting example, removal of Boc can be accomplished with trifluoroacetic acid or hydrochloric acid. Compound 1.3b is coupled with the amino acid intermediate A m using HATU to give the intermediate peptide 1.3c. Sonogashira coupling of the intermediate peptide 1.3c and the alkynyl intermediate S gives the intermediate 1.3d. Compound 1.3d is then reacted with an acyl chloride to give the compound of formula I.

[0413] Examples 183 - 186 were prepared by this general strategy. Example 183 provides exemplary reaction conditions and reagents suitable for preparing the compounds of the present invention according to Scheme 1.3.

[0414] Scheme 1.4

[0415]

[0416] X 1 can be directly installed on the haloarene as shown in Scheme 1.4. In this example, the organic halide intermediate S L (as shown above, where L is iodine, bromine or chlorine) is coupled with compound 1.4a via a Borylation - Suzuki reaction. Examples 188 - 201 were prepared using the method shown in Scheme 1.4. Exemplary reaction conditions are found in Example 188.

[0417] Scheme 1.5

[0418]

[0419] Alternatively, the installation of X 1 can be achieved by metal - catalyzed coupling of boric acid or borate ester (intermediate S b ) with compound 1.5a. This reaction is carried out using XPhos Pd G2. Xphos, also known as XPhos, is 2 - dicyclohexylphosphino - 2′,4′,6′ - triisopropylbiphenyl. Pd G2 is chloro(2 - dicyclohexylphosphino - 2′,4′,6′ - triisopropyl - 1,1′ - biphenyl)[2 - (2′ - amino - 1,1′ - biphenyl)]palladium(II). Examples 202 - 211 and 218 were prepared according to Scheme 1.5. Example 202 provides exemplary reaction conditions for this transformation.

[0420] Scheme 1.6

[0421]

[0422] Example 212 was prepared according to Scheme 1.6. Example 212 provides exemplary reaction conditions for the transformation according to Scheme 1.6.

[0423] Scheme 1.7

[0424]

[0425] Scheme 1.7 shows an example of Suzuki cross-coupling followed by Boc deprotection and amide bond formation. Exemplary reaction conditions can be found in Example 213. Examples 214 - 217 show the installation of different R 2 and R 3 groups.

[0426] Scheme 1.8

[0427]

[0428] Scheme 1.8 shows the general synthesis of compounds within the scope of formula I, starting from the reductive amination of compound 1.8a with a substituted benzaldehyde (intermediate P). Reductive amination of compound 1.8a with the substituted benzaldehyde intermediate P gives compound 1.8b. As a non-limiting example, the reductive amination can be accomplished with sodium cyanoborohydride. Subsequently, the epoxide of ((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamic acid tert-butyl ester is ring-opened to give compound 1.8c. Subsequently, Boc is removed, followed by formation of the amide bond to give compound 1.8d. As a non-limiting example, the removal of Boc can be accomplished with trifluoroacetic acid or hydrochloric acid. As a non-limiting example, the formation of the amide bond can be accomplished with a carboxylic acid and a reagent such as HATU. Subsequently, the protecting group is removed to give compound 1.8e. Subsequently, the amide bond is formed to give compound 1.8f. As a non-limiting example, the formation of the amide bond can be accomplished with a carboxylic acid and a reagent such as HATU. Subsequently, metal-catalyzed coupling, such as Sonogashira- or Suzuki-coupling, can be carried out. The Sonogashira coupling of compound 1.8d with the alkynyl intermediate S a gives the compound of formula I.

[0429] Examples 221 - 223 were prepared by this general strategy.

[0430] 2. Synthetic Intermediates

[0431] 2.1 Synthesis of P Intermediate

[0432]

[0433] 4-(1-(Difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzaldehyde (P1). 4-Bromo-1H-imidazole (1 g, 6.8 mmol), cesium carbonate (44430 mg, 136.36 mmol), and difluoroiodomethane (10% wt. in THF, 20 ml, 10.62 mmol) in a suspension in a 75 mL sealed vessel were heated at 50 °C overnight. The reaction mixture was cooled to room temperature and then filtered through Celite. The filter cake was washed with EtOAc. The filtrate was washed with brine, dried over sodium sulfate, and carefully concentrated. The residue was purified by silica gel column chromatography (17% to 47% EtOAc / Hex) to give 1.3 g of a mixture of positional isomers. This mixture was combined with 3,5-difluoro-4-formylphenylboronic acid (1.6 g, 8.58 mmol), XPhos Pd G2 (0.4 g, 0.26 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (0.12 g, 0.26 mmol), tripotassium phosphate (2 M, 3.3 ml) in dioxane (11 ml), degassed with argon for 10 minutes, and then heated at 100 °C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed 2x with brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (23% to 92% EtOAc / Hex) to give the desired isomer P1. MS (ESI) m / z 259.2 [M+H] + . 1 1H NMR (400 MHz, chloroform-d) δ 10.32 (d, J = 1.1 Hz, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.63 (d, J = 1.3 Hz, 1H), 7.48 - 7.36 (m, 2H), 7.16 (t, J = 60.8 Hz, 1H).

[0434]

[0435] 4-(1-(Difluoromethyl)-1H-imidazol-4-yl)benzaldehyde (P2). The title compound P2 was prepared according to the method provided for the synthesis of intermediate P1, but using (4-formylphenyl)boronic acid instead. MS (ESI) m / z 223.2 [M+H] + . 1 1H NMR (400 MHz, chloroform-d) δ 10.02 (s, 1H), 8.01 - 7.89 (m, 5H), 7.62 (d, J = 1.3 Hz, 1H), 7.15 (t, J = 60.9 Hz, 1H).

[0436]

[0437] 4-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzaldehyde (P3). Due to the exothermic reaction, 5-cyclopropyl-1,3,4-thiadiazol-2-amine (2 g, 14.16 mmol) was slowly added to a heterogeneous solution of copper(II) bromide (3.8 g, 17 mmol) and tert-butyl nitrite (2.53 mL, 21.25 mmol) in MeCN (78 mL) in a three-necked flask equipped with a stir bar and a sidewall inlet under argon, and the mixture was stirred overnight at room temperature and under argon. The reaction mixture was quenched with 78 mL of saturated NH4Cl (aqueous) and extracted with diethyl ether. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10% to 50% EtOAc / Hex). The product (0.28 g, 1.34 mmol) was combined with 3,5-difluoro-4-formylphenylboronic acid (0.5 g, 2.69 mmol), XPhos Pd G2 (0.15 g, 0.09 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (45.06 mg, 0.09 mmol), and tripotassium phosphate (2 M, 1.34 mL) in dioxane (4.9 mL), degassed with argon for 10 minutes, and then heated at 100 °C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed twice with brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (21% to 100% EtOAc / Hex) to afford the desired isomer P3. MS (ESI) m / z 267.1 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 10.37 (s, 1H), 7.56 (d, J = 9.0 Hz, 2H), 5.30 (d, J = 0.7 Hz, 0H), 2.47 (dt, J = 8.1, 3.7 Hz, 1H), 1.55 (s, 5H), 1.33 (dd, J = 8.3, 4.1 Hz, 2H), 1.26 (d, J = 4.4 Hz, 5H), 0.92 - 0.79 (m, 2H).

[0438]

[0439] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P4) In a 150 mL pressure vessel, a suspension of 3-bromo-1H-pyrazole (8 g, 54.43 mmol), cesium carbonate (53.2 g, 163.29 mmol) and difluoroiodomethane (10% wt. in THF, 200 mL, 106.23 mmol) was heated at 45 °C overnight. The reaction mixture was cooled to room temperature and then filtered through Celite. The filter cake was washed with Et2O (3 x 150 mL). The filtrate was washed with brine, dried over sodium sulfate and carefully concentrated (20 °C bath, 100 mb vacuum) to give approximately 17 g of positional isomers in a 1.5:1 ratio, still containing solvent. This crude material was combined with 3,5-difluoro-4-formylphenylboronic acid (12.65 g, 68.03 mmol), palladium acetate (0.31 g, 1.381 mmol), butyldi-1-adamantylphosphine (1.171 g, 3.265 mmol) and potassium carbonate (22.80 g, 164.96 mmol) in dioxane (150 mL) and water (50 mL). The mixture was degassed with argon for 10 minutes and then heated at 100 °C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine 2 x, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (5% to 15% EtOAc / Hex). The combined fractions of the mixed grades were recrystallized (5:1 Hex / EtOAc) to give the pure product P4. 1 1H NMR (400 MHz, chloroform-d) δ 10.35 (d, J = 1.0 Hz, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.46 (d, J = 9.6 Hz, 2H), 7.24 (t, J = 60.5 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H).

[0440]

[0441] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2-fluorobenzaldehyde (P5). The preparation of the title compound P5 was carried out according to the method proposed for the synthesis of intermediate P4, but using (3-fluoro-4-formylphenyl)boronic acid instead. 1 1H NMR (400 MHz, chloroform-d) δ 10.41 (s, 1H), 7.97 (dd, J = 8.0, 7.1 Hz, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.50–7.34 (m, 2H), 6.55 (d, J = 1.7 Hz, 1H).

[0442]

[0443] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)benzaldehyde (P6). The preparation of the title compound P6 was carried out according to the method proposed for the synthesis of intermediate P4, but using (4-formylphenyl)boronic acid instead. 1 1H NMR (400 MHz, chloroform-d) δ 10.05 (s, 1H), 8.03–7.93 (m, 4H), 7.90 (d, J = 2.7 Hz, 1H), 6.85 (d, J = 2.7 Hz, 1H).

[0444]

[0445] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzaldehyde (P7). A suspension of 1-difluoromethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.47 g, 6.03 mmol), 4-bromo-2,6-difluorobenzaldehyde (1.1 g, 4.98 mmol), palladium(II) acetate (0.03 g, 0.12 mmol), butyldi-1-adamantylphosphine (0.11 g, 0.3 mmol) and potassium carbonate (2.06 g, 14.93 mmol) in water (7 ml) and 1,4-dioxane (22 ml) in a tube was degassed with argon for 10 minutes, then the tube was sealed and heated at 100 °C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed 2x with brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (10% to 25% EtOAc / Hex) to give P7. 1 1H NMR (400 MHz, chloroform-d) δ 10.32 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.23 (t, J = 60.4 Hz, 1H), 7.14 (d, J = 9.5 Hz, 2H).

[0446]

[0447] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorobenzaldehyde (P8). The preparation of the title compound P8 was carried out according to the method proposed for the synthesis of intermediate P7, but using 4-bromo-2-fluorobenzaldehyde instead. 11H NMR (400 MHz, chloroform-d) δ 10.35 (d, J = 0.7 Hz, 1H), 8.15 (d, J = 0.7 Hz, 1H), 7.98 (q, J = 0.8 Hz, 1H), 7.91 (dd, J = 8.1, 7.3 Hz, 1H), 7.42 (ddd, J = 8.1, 1.7, 0.8 Hz, 1H), 7.31 (dd, J = 11.3, 1.6 Hz, 1H), 7.23 (s, 1H).

[0448]

[0449] Synthesis of 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzaldehyde (P9). The title compound P9 was prepared according to the method proposed for the synthesis of intermediate P7, but using 4-bromobenzaldehyde instead. 1 1H NMR (400 MHz, chloroform-d) δ 10.02 (s, 1H), 8.16 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.96–7.90 (m, 2H), 7.71–7.66 (m, 2H), 7.24 (t, J = 0.14 Hz, 1H).

[0450]

[0451] Synthesis of 3-bromo-1-(2,2-difluoroethyl)-1H-pyrazole (P10a) A solution of 1,1-difluoro-2-iodoethane (24.68 g, 128.59 mmol) was added dropwise via a dropping funnel to a solution of 3-bromo-1H-pyrazole (6 g, 42.86 mmol) and potassium carbonate (20.73 g, 150.03 mmol) in DMF (20 mL) at 35 °C. The reaction was stirred overnight, then cooled to room temperature, diluted with ether / hexane and washed with brine and NH4Cl solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (7% to 25% EtOAc / Hex) to give P10a (5.4 g, 63.6%). MS (ESI) m / z 211.0 [M+H] +。1H NMR (400 MHz, chloroform-d) δ 7.36 (d, J = 2.4 Hz, 1H), 6.32 (d, J = 2.4 Hz, 1H), 6.06 (tt, J = 55.4, 4.3 Hz, 1H), 4.41 (td, J = 13.3, 4.3 Hz, 2H). Synthesis of 4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P10) P10a (4.31 g, 0.02 mol) was combined with 3,5-difluoro-4-formylphenylboronic acid (4.96 g, 24.49 mmol), PdCl2(tBu2PPh)2 (570 mg, 0.92 mmol), and tripotassium phosphate monohydrate (1.0 M, 40.82 ml) in 2-methyltetrahydrofuran (20 mL) and water (20 mL). The mixture was degassed with argon for 10 minutes and then heated at 75 °C overnight. The reaction was cooled to room temperature, the organic layer was separated, and the aqueous layer was extracted into EtOAc. The combined organic layers were washed with 1 M HCl and then brine, filtered, concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine 2x, then dried over Na2SO4, filtered, and concentrated under reduced pressure, and recrystallized (1:3 EtOAc / hexane). The isolated solid contained a mixture of the desired isomer and unreacted boronic acid. This mixture was purified by silica gel column chromatography (70% to 100% DCM / Hex) to afford P10 (2.3 g, 41%) MS (ESI) m / z 273.1 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 10.34 (d, J = 1.0 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.47 - 7.38 (m, 2H), 6.67 (d, J = 2.4 Hz, 1H), 6.15 (tt, J = 55.3, 4.3 Hz, 1H), 4.52 (td, J = 13.5, 4.3 Hz, 2H).

[0452]

[0453] Synthesis of 4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2-fluorobenzaldehyde (P11). The title compound P11 was prepared according to the method described for the synthesis of intermediate P10, but using (3-fluoro-4-formylphenyl)boronic acid in place of the latter. 1HNMR (400 MHz, chloroform-d) δ 10.34 (d, J = 0.8 Hz, 1H), 7.89 (dd, J = 8.1, 7.2 Hz, 1H), 7.70–7.58 (m, 2H), 7.54 (d, J = 2.4 Hz, 1H), 7.33 (dt, J = 8.0, 1.0 Hz, 0H), 7.26 (dd, J = 10.7, 1.5 Hz, 0H), 6.68 (d, J = 2.4 Hz, 1H), 6.42 (d, J = 1.9 Hz, 0H), 6.15 (tt, J = 55.4, 4.3 Hz, 1H), 4.52 (td, J = 13.5, 4.3 Hz, 2H).

[0454]

[0455] Synthesis of 4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)benzaldehyde (P12). The title compound P12 was prepared according to the method proposed for the synthesis of compound P10, but using (4-formylphenyl)boronic acid as an alternative. MS (ESI) m / z 273.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 10.34 (d, J = 1.0 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.47 - 7.38 (m, 2H), 6.67 (d, J = 2.4 Hz, 1H), 6.15 (tt, J = 55.3, 4.3 Hz, 1H), 4.52 (td, J = 13.5, 4.3 Hz, 2H).

[0456]

[0457] Synthesis of 4-(1-cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P13) A suspension of anhydrous copper(II) acetate (3.7 g, 20.41 mmol) and 2,2'-bipyridine (3.2 g, 20.41 mmol) in DCE (40 mL) was degassed, warmed to 50 °C, and stirred for 10 minutes, then added to 3-bromo-1H-pyrazole (3 g, 20.41 mmol), cyclopropylboronic acid (5.3 g, 20.41), and sodium carbonate (4.8 g, 44.91 mmol) in DCE (60 mL). The reaction was stirred at 65 °C for 48 h. The reaction mixture was cooled to room temperature, filtered through a Celite sinter, and rinsed with EtOAc. The filtrate was concentrated under reduced pressure, the residue was partitioned between EtOAc and NH4Cl solution, the organic layer was washed with NH4Cl, Na2CO3 solution brine, dried over Na2SO4 and purified by silica gel column chromatography (10% to 35% EtOAc / Hex) to give 3-bromo-1-cyclopropyl-1H-pyrazole.

[0458] 3-Bromo-1-cyclopropyl-1H-pyrazole (1.5 g, 8.18 mmol) was combined with 3,5-difluoro-4-formylphenylboronic acid (1.8 g, 9.8 mmol), PdCl2(tBu2PPh)2 (0.29 g, 0.41 mmol), and tripotassium phosphate monohydrate (4.71 g, 20.45 mmol) in 2-methyltetrahydrofuran (60 mL) and water (60 mL), degassed with argon for 10 minutes, and then heated to reflux for a total of 3 h. The reaction mixture was cooled to room temperature, the organic layer was separated, and the aqueous layer was extracted into EtOAc. The combined organic layers were washed with 1 M HCl and then brine, filtered, and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with brine 2x, then dried over Na2SO4, filtered, and concentrated under reduced pressure. This mixture was purified by silica gel column chromatography (50% to 100% DCM / Hex - 10% EtOAc / DCM) to afford P13 (1.2 g, 49%). MS (ESI) m / z 249.2 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 10.33 (s, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 10.1 Hz, 2H), 6.57 (d, J = 2.4 Hz, 1H), 3.66 (tt, J = 7.4, 3.9 Hz, 1H), 1.26 - 1.15 (m, 2H), 1.09 (qd, J = 5.7, 2.4 Hz, 2H).

[0459]

[0460] Synthesis of 2,6-difluoro-4-(4-fluoropyridin-2-yl)benzaldehyde (P14). A suspension of 2-bromo-5-fluoropyridine (0.95 g, 5.39 mmol), 3,5-difluoro-4-formylphenylboronic acid (0.8 g, 4.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (302 mg, 0.43 mmol), and potassium carbonate (1.49 g, 10.76 mmol) in a mixture of DME (10 ml) and water (5 ml) was degassed with argon for 10 minutes and then heated at 85 °C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with EtOAc and washed with brine 2x, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (10% to 20% EtOAc / Hex) to afford P14 (122 mg, 12%). MS (ESI) m / z 238.1 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 10.38 (d, J = 1.2 Hz, 1H), 8.59 (d, J = 2.8 Hz, 1H), 7.78 (ddd, J = 8.8, 4.2, 0.6 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.55 (ddd, J = 8.8, 7.8, 2.9 Hz, 1H).

[0461]

[0462] Synthesis of 2,6-difluoro-4-(4-fluoropyridin-2-yl)benzaldehyde (P15). The title compound P15 was prepared according to the method proposed for the synthesis of compound P14, but using 2-bromo-4-fluoropyridine instead. MS (ESI) m / z 238.2 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 10.39 (s, 1H), 8.70 (dd, J = 8.6, 5.5 Hz, 1H), 7.67 (d, J = 9.9 Hz, 3H), 7.48 (dd, J = 9.8, 2.3 Hz, 1H), 7.11 (ddd, J = 7.9, 5.5, 2.3 Hz, 1H).

[0463]

[0464] Synthesis of 2,6-difluoro-4-(pyrimidin-2-yl)benzaldehyde (P16). 2-Bromopyrimidine (1 g, 6.29 mmol) and tetrakis(triphenylphosphine)palladium (218.05 mg, 0.19 mmol) in 1,2-dimethoxyethane (30 ml) were degassed for 5 minutes, then water (15 ml) was added, followed by 3,5-difluoro-4-formylphenylboronic acid (1.4 g, 7.55 mmol) and sodium bicarbonate (1.0 M in THF, 1.59 g, 18.87 mmol). The reaction mixture was heated at 85 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated NaHCO3 solution and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0% to 40% EtOAc / Hex to give P16. 1 1H NMR (400 MHz, chloroform-d) δ 10.42 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 4.9 Hz, 2H), 8.16–8.03 (m, 2H), 7.32 (t, J = 4.8 Hz, 1H).

[0465]

[0466] (S)-2,6-Difluoro-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)benzaldehyde (P17) Sodium hydride (60% oil dispersion, 241 mg, 6.03 mmol) was added to a solution of 3-bromo-1H-pyrazole (583 mg, 3.97 mmol) in DMF (15 mL) cooled in an ice bath. After stirring for 1.5 h, a solution of (R)-tetrahydrofuran-3-yl methanesulfonate (reference: PCT International Application 2013068458) (998 mg, 6.01 mmol) in DMF (5 mL) was added and the reaction mixture was heated to 100 °C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, concentrated in vacuo and the crude residue was purified by silica gel column chromatography (20% to 40% EtOAc / Hex to give (S)-3-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazole (0.17 g, 0.78 mmol). This material was combined in a 20 mL microwave tube with 3,5-difluoro-4-formylphenylboronic acid (0.19 g, 1 mmol), palladium acetate (6.5 mg, 0.03 mmol), butyldi-1-adamantylphosphine (21.4 mg, 0.06 mmol) and potassium carbonate (0.33 g, 2.4 mmol) in a mixture of water (2 ml) and 1,4-dioxane (6 ml). The mixture was degassed with argon for 5 minutes. The reaction was microwave irradiated at 100 °C for 1.5 h, then cooled to room temperature, concentrated in vacuo, then diluted with EtOAc and washed with water and brine. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure. This mixture was purified by silica gel column chromatography (20% to 40% EtOAc / hex) to give P17. MS (ESI) m / z 279.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 10.32 (d, J = 1.0 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.48 - 7.34 (m, 2H), 6.62 (d, J = 2.4 Hz, 1H), 5.03 (ddt, J = 8.2, 5.8, 3.4 Hz, 1H), 4.31 - 4.03 (m, 4H), 3.98 (td, J = 8.6, 5.5 Hz, 1H), 2.51 (dtd, J = 13.4, 8.3, 7.1 Hz, 1H), 2.43 - 2.28 (m, 1H).

[0467]

[0468] (R)-2,6-Difluoro-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)benzaldehyde (P18). The preparation of the title compound P18 was carried out according to the method proposed for the synthesis of compound P17, but using (S)-tetrahydrofuran-3-yl methanesulfonate instead (reference: PCT International Application 2013068458). MS (ESI) m / z 279.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 10.34 (d, J = 1.1 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.50 - 7.33 (m, 2H), 6.63 (d, J = 2.4 Hz, 1H), 5.04 (ddt, J = 9.0, 6.6, 3.5 Hz, 1H), 4.27 - 4.04 (m, 4H), 3.99 (td, J = 8.6, 5.5 Hz, 1H), 2.52 (dtd, J = 13.3, 8.2, 7.1 Hz, 1H), 2.38 (dddd, J = 13.3, 8.0, 5.5, 3.4 Hz, 1H).

[0469]

[0470] 2,6-Difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)benzaldehyde (P19) The preparation of the title compound P19 was carried out according to the method proposed for the synthesis of compound P4, but using 1-chloro-2-methylpropan-2-ol instead. MS (ESI) m / z 281.0 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 10.33 (s, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.47–7.35 (m, 2H), 6.64 (d, J = 2.4 Hz, 1H), 4.13 (s, 2H), 1.22 (s, 7H).

[0471]

[0472] Synthesis of 2,6-difluoro-4-(2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)benzaldehyde (P20). A suspension of S7a (0.14 g, 3.7 mmol), (3,5-difluoro-4-formylphenyl)boronic acid (110.29 mg, 5.9 mmol), potassium carbonate (0.15 g, 1 mmol) and tetrakis(triphenylphosphine)palladium (20 mg, 0.19 mmol) in a mixture of dioxane (15 ml) and water (15 ml) was degassed for 10 minutes. The reaction mixture was heated at 85 °C for 3 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated NaHCO3 solution and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0% to 40% EtOAc / Hex) to give P20 (99 mg, 62%). MS (ESI) m / z 387.2 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 10.33 (s, 1H), 8.55 (s, 1H), 7.11 (d, J = 9.8 Hz, 1H), 4.74 (t, J = 6.3 Hz, 1H), 4.61 (s, 1H), 4.40 (d, J = 12.8 Hz, 1H), 3.69 (s, 1H), 3.33 - 3.02 (m, 3H), 1.86 (s, 1H), 1.65 (d, J = 8.1 Hz, 1H), 1.55 (s, 2H).

[0473]

[0474] Synthesis of 4-(1-cyclopropyl-1H-pyrazol-3-yl)benzaldehyde (P21). The title compound P21 was prepared according to the method described for the synthesis of compound P13, but using (4-formylphenyl)boronic acid as an alternative. MS (ESI) m / z 213.2 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 10.01 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.92 - 7.86 (m, 2H), 7.50 (d, J = 2.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 3.66 (tt, J = 7.4, 3.8 Hz, 1H), 1.22 - 1.15 (m, 2H), 1.11 - 1.03 (m, 2H).

[0475]

[0476] Synthesis of 2,6-difluoro-4-(6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)benzaldehyde (P22) S4a (0.53 g, 1 mmol), (3,5-difluoro-4-formylphenyl)boronic acid (413.8 mg, 2.0 mmol), potassium carbonate (0.16 g, 4 mmol) and Cl2Pd(tBu2PPh)2 (0.02 g, 0.37 mmol) were degassed for 10 minutes in a suspension in a mixture of dioxane (15 ml) and water (15 ml). The reaction mixture was heated at 60 °C for 3 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated NaHCO3 solution and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (1% to 15% (MeOH / (1% E3N in EtOAc)) to give P22 (470 mg, 85%). MS (ESI) m / z 372.2 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 10.34 (s, 1H), 8.52 (d, J = 2.5 Hz, 1H), 7.76 (dd, J = 8.9, 2.5 Hz, 1H), 7.16 (d, J = 10.4 Hz, 2H), 6.61 (d, J = 8.8 Hz, 1H), 4.71 (t, J = 6.2 Hz, 2H), 4.50 (s, 2H), 3.87 (t, J = 6.2 Hz, 3H), 3.57 (s, 4H), 2.78 (d, J = 7.3 Hz, 1H), 1.64 (d, J = 8.9 Hz, 1H).

[0477]

[0478] Synthesis of 2,6-difluoro-4-(6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)benzaldehyde (P23) The title compound P23 was prepared according to the method described for the synthesis of compound P20, but using S3c instead. MS (ESI) m / z 386.1 [M+H] + 。

[0479]

[0480] Synthesis of 2,6-dichloro-4-(pyridin-2-yl)benzaldehyde (P24) and 2-chloro-4-(pyridin-2-yl)benzaldehyde (P25). In a sealed tube, methyl 4-bromo-2,6-dichlorobenzoate (3.18 g, 11.2 mmol), 2-(trimethylstannyl)pyridine (1.94 mL, 11.2 mmol), and tetrakis(triphenylphosphine)palladium (647.1 mg, 0.56 mmol) were suspended in DMF (25 mL). The mixture was degassed with argon for 10 minutes, heated to 100 °C for 18 hours, and then allowed to reach room temperature. After 48 h, the reaction was diluted with EtOAc and washed with KF (3 g in 50 mL of water) and brine (3x), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0% to 20% EtOAc / hexane) to afford methyl 2,6-dichloro-4-(pyridin-2-yl)benzoate (1.5 g, 47.5%). This material was dissolved in THF (25 mL), cooled to 0 °C, and then lithium aluminum hydride (0.4 g, 10.63 mmol) was added slowly. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 h, then cooled back to 0 °C, water (500 μL) (vigorous gas evolution) was added slowly, followed by NaOH (2 M, 500 μL), and then water (1500 μL). The slurry was stirred at room temperature. After 1 h, Na2SO4 was added, and then the mixture was filtered through Celite. The solid was rinsed with Et2O (~200 mL), and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue (1.5 g, 5.9 mmol) was combined with pyridinium chlorochromate (1.91 g, 8.85 mmol) and Celite (700 mg, 7 mmol), DCM (10 mL) was added, and the reaction mixture was stirred at room temperature for 48 h. The reaction was filtered through a Celite frit with a small plug of silica and rinsed several times with DCM / EtOAc, then the filtrate was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to afford P24 (392 mg, 26.3%). MS (ESI) m / z 252.0 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 10.54 (s, 1H), 8.74 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.06 (s, 2H), 7.83 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H), 7.77 (dt, J = 8.0, 1.1 Hz, 1H), 7.36 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H) and P25 (195 mg, 15.2%). MS (ESI) m / z 218.1 [M+H]+ 。1H NMR (400 MHz, chloroform-d) δ 10.52 (d, J = 0.8 Hz, 1H), 8.74 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H), 8.17 (dd, J = 1.6, 0.5 Hz, 1H), 8.07 - 7.95 (m, 2H), 7.91 - 7.75 (m, 2H), 7.39 - 7.29 (m, 1H).

[0481]

[0482] Synthesis of 4-bromo-2,6-difluorobenzaldehyde (P26a) To a solution of methyl 4-bromo-2-chloro-6-fluorobenzoate (5.6 g, 20.94 mmol) in DCM (100 mL) at -78 °C was added dropwise diisobutylaluminum hydride (1.0 M in toluene, 60 mL). After 4.5 h, the reaction mixture was quenched with MeOH (2.4 mL), then NaOH (6.0 M, 2.4 mL), and then water (5 mL). The reaction was stirred for 1 h, then Na2SO4 was added, filtered, and concentrated in vacuo. The residue (4.96 g, 20.71 mmol) was dissolved in DCM (100 mL) and cooled to 5 °C, then pyridinium chlorochromate (6.27 g, 0.03 mol) was added and the mixture was stirred overnight, allowing it to warm slowly to room temperature. Silica gel (10 g) was added, and the mixture was filtered through a 1.5-inch silica gel plug, eluting with 5:1 DCM / EtOAc to give P26a (4.67 g, 92%). 1 H NMR (400 MHz, chloroform-d) δ 10.38 (s, 1H), 7.54 - 7.41 (m, 1H), 7.31 (dd, J = 9.7, 1.8 Hz, 1H). 19 F NMR (377 MHz, chloroform-d) δ -113.31 (d, J = 9.7 Hz).

[0483] Synthesis of 2-chloro-6-fluoro-4-(pyridin-2-yl)benzaldehyde (P26) At room temperature, 2-pyridylzinc bromide (0.5 M in THF, 28.43 ml) was added to a solution of P26a (2.5 g, 10.53 mmol) and Pd(tBu2PPh)2Cl2 (213 mg, 0.34 mmol) in methyltetrahydrofuran (7 mL). The reaction was degassed with Ar for 10 minutes and then heated to 60 °C. After 3 h, the mixture was cooled to room temperature, diluted with EtOAc and washed with a saturated solution of NH4Cl. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (3%-35% EtOAc in 1:1 DCM / hexane) to give P26 (1.09 g, 41%) MS (ESI) m / z 236.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 10.49 (d, J = 1.1 Hz, 1H), 8.74 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 7.96 (t, J = 1.4 Hz, 1H), 7.86 (d, J = 1.8 Hz, 0H), 7.85 - 7.80 (m, 1H), 7.78 (q, J = 1.1 Hz, 1H), 7.77 - 7.74 (m, 1H), 7.36 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H). 19 F NMR (377 MHz, chloroform-d) δ -114.35 (d, J = 11.6 Hz).

[0484]

[0485] Synthesis of 4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-2,6-difluorobenzaldehyde (P27). 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (1 g, 0.01 mol) in CH3CN (5 mL) was combined with cuprous bromide (1.24 g, 0.01 mol) and copper(II) bromide (16.05 mg, 0.07 mmol) at 15 °C, then tert-butyl nitrite (1.11 ml, 0.01 mol) was added very slowly and the reaction was stirred overnight. The mixture was quenched with aqueous NH4Cl, diluted with DCM, the layers were separated, and the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (7%-40% EtOAc / hexane), and the product (0.59 g, 2.91 mmol) was combined with 3,5-difluoro-4-formylphenylboronic acid (0.81 g, 4.36 mmol), PdCl2(tBu2PPh)2 (0.08 g, 0.12 mmol) and tripotassium phosphate monohydrate (1.67 g, 7.27 mmol) in 2-methyltetrahydrofuran (25 mL) and water (60 mL), degassed with argon for 10 minutes, then heated to reflux for a total of 3 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water, 5% citric acid solution and brine. The separated organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was crystallized from EtOAc / ether to give P27 (486 mg, 63%) MS (ESI) m / z 265.1 [M+H] + 。

[0486]

[0487] Synthesis of 2,6-difluoro-4-(pyridin-2-yl)benzaldehyde (P28). The title compound P28 was prepared according to the method proposed for the synthesis of compound P20, but 2-bromopyridine was used instead. MS (ESI) m / z 202.2 [M+H] + 。

[0488]

[0489] Synthesis of 2,6-difluoro-4-(pyridin-2-yl)benzaldehyde (P29). The title compound P29 was prepared according to the method proposed for the synthesis of compound P20, but 2-bromopyridine and (3-fluoro-4-formylphenyl)boronic acid were used instead. MS (ESI) m / z 220.2 [M+H] + 。

[0490]

[0491] Synthesis of 4-(pyridin-2-yl)benzaldehyde (P30). The preparation of the title compound P30 was carried out according to the method proposed for the synthesis of compound P20, but 2-bromopyridine and (4-formylphenyl)boronic acid were used instead. MS(ESI) m / z 184.1 [M+H] + 。

[0492]

[0493] Synthesis of bicyclo[2.2.1]heptane-1-carbaldehyde (P31) Bicyclo[2.2.1]heptane-1-carboxylic acid (1000 mg, 0.01 mol) was dissolved in methyltetrahydrofuran (3 mL), cooled to 0 °C, and then lithium aluminum hydride (0.5 g, 14 mmol) was slowly added. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 2 h. The mixture was cooled back to 0 °C, water (540 μL) (vigorous gas evolution) was slowly added, followed by NaOH (2 M, 540 μL), and then water (1500 μL). The slurry was stirred at room temperature. After 1 h, Na2SO4 was added, and then the mixture was filtered through Celite. The solid was rinsed with DCM (~200 mL), and the filtrate was concentrated under reduced pressure. The crude residue (900 mg, 7.13 mmol) was dissolved in DCM (10 mL), cooled in an ice bath, and combined with pyridinium chlorochromate (2.61 g, 12.12 mmol) and Celite (700 mg, 7 mmol), and the reaction was slowly warmed to room temperature and stirred for 48 h. The reaction was filtered through a Celite sinter with a small silica plug and rinsed several times with DCM, and then the filtrate was concentrated under reduced pressure and at 5 °C to give P31 (1.7 g, 95%). 1 H NMR (400 MHz, chloroform-d) δ 9.85 (s, 1H), 2.41 (td, J = 4.2, 2.1 Hz, 1H), 2.04 - 1.27 (m, 10H).

[0494]

[0495] Synthesis of 2,6-difluoro-4-(oxetan-3-yl)benzaldehyde (P32) In a sealed tube, 3-iodo-oxetane (0.24 ml, 3 mmol), (3,5-difluoro-4-formylphenyl)boronic acid (250 mg, 1.34 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (18.05 mg, 0.07 mmol), Ni(NO3)2·6H2O (19.55 mg, 0.07 mmol) and potassium carbonate (557.51 mg, 4.03 mmol) were combined in 1,4-dioxane (5 ml). The mixture was degassed with argon for 10 minutes, heated to 80 °C for 12 hours, and then cooled to room temperature. After 48 h, the reaction was diluted with EtOAc and washed with brine (2x), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (10% to 30% EtOAc / hexane) to give P32 (49 mg, 18%). 1 1H NMR (400 MHz, chloroform-d) δ 10.26 (d, J = 1.2 Hz, 1H), 6.99 (d, J = 9.5 Hz, 2H), 5.04 (dd, J = 8.2, 6.3 Hz, 2H), 4.62 (t, J = 6.3 Hz, 2H), 4.14 (tt, J = 8.2, 6.2 Hz, 1H).

[0496]

[0497] Synthesis of 2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)benzaldehyde (P33) 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester (414.48 mg, 1.97 mmol), 4-bromo-2,6-difluorobenzyl alcohol (0.4 g, 2 mmol), tetrakis(triphenylphosphine)palladium (103.63 mg, 0.09 mmol) and sodium carbonate (2 M, 2.24 mL) were combined in 1,4-dioxane (6 ml). The mixture was degassed with argon for 10 minutes, heated to 80 °C for 12 hours, and then cooled to room temperature. The reaction was diluted with EtOAc, washed with brine (2x), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20% to 50% EtOAc / hexane), the product (405 mg, 1.79 mmol) was dissolved in EtOAc (8 mL), palladium (10% on C, 38.1 mg, 0.36 mmol) was added and the mixture was stirred at room temperature under hydrogen for 18 h. The mixture was filtered through Celite and rinsed several times with EtOAc, and the filtrate was concentrated under reduced pressure.

[0498] The crude residue (450 mg, 1.97 mmol) was dissolved in DCM (10 mL) and combined with pyridinium chlorochromate (637.49 mg, 2.96 mmol). The reaction was stirred at room temperature for 48 h. The reaction was then filtered through Celite and rinsed several times with DCM. The filtrate was concentrated under reduced pressure to afford P33. 1H NMR (400 MHz, chloroform-d) δ 10.28 (d, J = 1.2 Hz, 1H), 6.85 (d, J = 10.0 Hz, 2H), 4.08 (dt, J = 11.5, 3.2 Hz, 2H), 3.60–3.33 (m, 2H), 2.90–2.71 (m, 1H), 1.83–1.70 (m, 4H).

[0499]

[0500] Synthesis of 2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde (P34). The title compound P34 was prepared according to the method proposed for the synthesis of compound P1, but 2-bromo-5-methyl-1,3,4-oxadiazole was used instead. MS (ESI) m / z 225.1 [M+H] + 。

[0501]

[0502] Synthesis of 4-(5-(difluoromethyl)pyridin-2-yl)-2,6-difluorobenzaldehyde (P35). The title compound P35 was prepared according to the method proposed for the synthesis of compound P1, but 2-bromo-5-(difluoromethyl)pyridine was used instead. MS (ESI) m / z 270.1 [M+H] + 。

[0503]

[0504] Synthesis of 2,6-difluoro-4-(pyrazin-2-yl)benzaldehyde (P36). A mixture of 4-bromo-2,6-difluorobenzaldehyde (2 g, 9.05 mmol), bis(pinacolato)diboron (3.22 g, 12.67 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane (739.04 mg, 0.9 mmol) and potassium acetate (1776.34 mg, 18.1 mmol) in 1,4-dioxane (18 mL) was heated to 90 °C for 12 h. After cooling to room temperature, 2-bromopyrazine (1.64 ml, 18.1 mmol), tetrakis(triphenylphosphine)palladium (1.05 g, 0.9 mmol) and potassium carbonate (2 M, 11.31 ml) were added. The mixture was degassed by evacuation and backfilled with Ar (3x), then the reaction was heated to 90 °C for 12 h, cooled to room temperature, diluted with EtOAc and washed with saturated brine solution. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0%-100% EtOAc / DCM / ) to give P36 MS (ESI) m / z 221.1 [M+H] + .

[0505]

[0506] Synthesis of 4-(5-fluoropyridin-2-yl)benzaldehyde (P37). The title compound P37 was prepared according to the method proposed for the synthesis of compound P14, but using (4-formylphenyl)boronic acid instead. MS (ESI) m / z 202.14 [M+H]+.

[0507]

[0508] Synthesis of 4-ethynyl-2,6-difluorobenzaldehyde (P38). A solution of 4-bromo-2,6-difluorobenzaldehyde reagent 2 (6 g, 27.15 mmol), CuI (517.06 mg, 2.71 mmol), PdCl2(tBu2PPh)2 (955.53 mg, 1.36 mmol), and trimethylsilylacetylene (7.67 ml, 54.3 mmol) in a 3:1 mixture of CH3CN (50 mL) / Et3N (10 mL) was degassed with argon for 10 minutes. The reaction mixture was heated to 70 °C for a total of 18 h. After cooling to room temperature, the mixture was filtered through silica gel, the filtrate was concentrated and purified by silica gel column chromatography (1%-15% EtOAc / Hex). The product was dissolved in MeOH (5 ml) and potassium carbonate (1876.01 mg, 13.57 mmol) was added. The mixture was stirred at room temperature. After 20 minutes, the reaction was concentrated to dryness, then diluted with DCM and washed with brine. The organic extract was dried over Na2SO4 to give p38 (2.99 g, 66%). 1 1H NMR (400 MHz, chloroform-d) δ 10.30 (d, J = 1.1 Hz, 1H), 7.04 (d, J = 9.1 Hz, 2H), 0.26 (s, 9H).

[0509]

[0510] Synthesis of 2,6-difluoro-4-(5-methylpyridin-2-yl)benzaldehyde (P39). The title compound P39 was prepared according to the method proposed for the synthesis of compound P16, but using 2-bromo-5-methylpyridine instead.

[0511]

[0512] Synthesis of 4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-difluorobenzaldehyde (P40). The title compound P40 was prepared according to the method proposed for the synthesis of compound P1, but using 2-bromo-5-cyclopropyl-1,3,4-oxadiazole instead. MS (ESI) m / z 251.1 [M+H] + 。

[0513]

[0514] Synthesis of 2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzaldehyde (P41) A solution of 3-bromo-1-methyl-1H-pyrazole (0.14 g, 3.7 mmol), (3,5-difluoro-4-formylphenyl)boronic acid (9.19 g, 49.43 mmol), sodium carbonate (8.72 g, 82.27 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.9 g, 1.64 mmol) in a mixture of 1,2-dimethoxyethane (84 ml) and water (36 ml) was degassed for 10 minutes. The reaction mixture was heated at 100 °C for 18 h. After cooling to room temperature, the mixture was diluted, concentrated in vacuo, then diluted with EtOAc and washed with brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20% to 40% EtOAc / Hex) to afford P41. MS (ESI) m / z 223.3 [M+H] + 。

[0515]

[0516] Synthesis of 2,6-difluoro-4-(1H-pyrazol-3-yl)benzaldehyde (P42). The title compound P42 was prepared according to the method described for the synthesis of compound P1, but using 3-bromo-1H-pyrazole instead. MS (ESI) m / z 209.1 [M+H] + 。

[0517]

[0518] Synthesis of 2,6-difluoro-4-(4-(oxetan-3-yloxy)pyridin-2-yl)benzaldehyde (P43). Oxetan-3-ol (0.42 ml, 6.66 mmol) was added dropwise to a suspension of NaH (60%, 310.79 mg, 7.77 mmol) in THF (11 ml). The mixture was stirred for 30 minutes and then 2-chloro-4-fluoropyridine (0.5 ml, 5.55 mmol) was added. The reaction mixture was stirred overnight, diluted with EtOAc and washed with water and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (30% to 60% EtOAc / Hex). The product (849 mg, 4.57 mmol) was combined with (3,5-difluoro-4-formylphenyl)boronic acid (1020.52 mg, 5.49 mmol), potassium carbonate (2 M, 5.49 ml) and Pd(dppf)Cl2 (279.29 mg, 0.46 mmol) in DME (23 ml). The mixture was degassed by evacuation and backfilled with Ar (5x), and heated to reflux for 3 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (30% to 60% EtOAc / Hex) to give P43 (1.22 g, 80%). MS (ESI) m / z 292.1 [M+H] + .

[0519]

[0520] Synthesis of 4-(1-(difluoromethyl)-1H-1,2,3-triazol-4-yl)-2,6-difluorobenzaldehyde (P44). 4-Ethynyl-2,6-difluorobenzaldehyde (1.5 g, 9.0 mmol) was dissolved in THF (10 mL). Copper(I) thiophene-2-carboxylate (115.71 mg, 0.9 mmol) was added over 5 minutes, followed by methyl azidomethyl pivalate (2.1 mL, 13.5 mmol). After 15 minutes, complete conversion was observed by LCMS analysis. The reaction was quenched with aqueous NaHCO3 and the intermediate product was extracted into ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was slurried in 40 mL of 1:1 MeOH:EtOH and aqueous NaOH solution (2 M, 9.9 mL, 19.9 mmol) was added. After 30 minutes, aqueous NaHCO3 was added and the intermediate product was extracted into ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was transferred to a 500 mL pressure vessel containing potassium carbonate (4.4 g, 32 mmol) and a magnetic stir bar using THF (20 mL). A solution of difluoroiodomethane (10% in THF, 68 mL, 36 mmol) was added and the vessel was sealed. The mixture was stirred at 50 °C overnight. The crude mixture was filtered, concentrated in vacuo and purified by flash column chromatography (0 → 25% EtOAc in 1:1 hexane:DCM). The desired positional isomer was the major component and was isolated in the middle fractions. 1 1H NMR (400 MHz, chloroform-d) δ 10.36 (s, 1H), 8.31 (s, 1H), 7.62 (t, J = 58.8 Hz, 1H), 7.59 - 7.51 (m, 2H). 19F NMR (377 MHz, chloroform-d) δ -95.78 (d, J = 58.9 Hz), -113.68 (d, J = 9.2 Hz).

[0521]

[0522] Synthesis of 4-(6-(difluoromethyl)pyridin-3-yl)-2,6-difluorobenzaldehyde (P45). The title compound P45 was prepared according to the method described for the synthesis of compound P16, but using 5-bromo-2-(difluoromethyl)pyridine instead. 1 1H NMR (400 MHz, chloroform-d) δ 10.40 (s, 1H), 8.94–8.79 (m, 1H), 8.04 (dd, J = 8.2, 2.3 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 9.3 Hz, 2H), 6.70 (t, J = 55.2 Hz, 1H). 1919F NMR (377 MHz, chloroform-d) δ -113.37 (d, J = 9.3 Hz), -116.56 (d, J = 55.5 Hz).

[0523]

[0524] Synthesis of 4-(1-cyclopropyl-1H-pyrazol-4-yl)benzaldehyde (P46). The title compound P46 was prepared according to the method proposed for the synthesis of compound P7, but using (4-formylphenyl)boronic acid and 4-bromo-1-cyclopropyl-1H-pyrazole instead. MS (ESI) m / z 213.2 [M+H] + 。

[0525]

[0526] Synthesis of 2,6-difluoro-4-(2-methylpyrimidin-5-yl)benzaldehyde (P47). The title compound P47 was prepared according to the method proposed for the synthesis of compound P16, but using 5-bromo-2-methylpyrimidine instead. MS (ESI) m / z 235.2 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 10.38 (t, J = 1.0 Hz, 1H), 8.86 (s, 2H), 7.30 - 7.14 (m, 3H), 2.82 (s, 3H).

[0527] 2.2 Synthesis of S Intermediate

[0528]

[0529] Synthesis of tert-butyl 7-(5-iodopyridin-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (S1a). A solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate (1 g, 4.38 mmol), 2-fluoro-5-iodopyridine (1.12 g, 5.04 mmol) and sodium carbonate (0.84 g, 7.88 mmol) in 1-methyl-2-pyrrolidone (4 ml) was heated at 85 °C overnight. The mixture was cooled to room temperature, diluted with water and extracted into DCM. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give S1a (1.57 g, 62.3%). MS (ESI) m / z 431.9 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 8.30 (dd, J = 2.4, 0.7 Hz, 1H), 7.66 (dd, J = 9.0, 2.3 Hz, 1H), 6.44 (d, J = 9.0 Hz, 1H), 4.25 (d, J = 12.7 Hz, 1H), 4.21 - 4.00 (m, 3H), 3.97 - 3.86 (m, 2H), 3.80 (t, J = 11.9 Hz, 2H), 3.26 (t, J = 15.1 Hz, 2H), 1.48 (s, 9H).

[0530] Synthesis of 7-(5-iodopyridin-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane (S1b). To a solution of S1a (1.57 g, 0.004 mol) in DCM (15 mL) in a water bath at room temperature was added HCl (4.0 M in dioxane, 4.6 mL). The reaction was stirred overnight at room temperature. The reaction was concentrated to dryness. MS (ESI) m / z 332.0 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.26 (dd, J = 2.2, 0.7 Hz, 1H), 8.22 (ddd, J = 9.5, 2.2, 1.0 Hz, 1H), 7.27 (d, J = 9.7 Hz, 1H), 4.60 (d, J = 14.4 Hz, 2H), 4.21 (dt, J = 13.5, 0.9 Hz, 2H), 4.08 (dt, J = 13.3, 2.4 Hz, 2H), 3.88 (d, J = 14.6 Hz, 2H), 3.81 (s, 2H).

[0531] Synthesis of 7-(5-iodopyridin-2-yl)-9-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane (S1c). To S1b (0.62 g, 8.62 mmol) suspended in NMP (6 mL) was added Et3N (0.12 ml, 0.8 mmol), oxetan-3-one (0.51 ml, 8.5 mmol) and sodium cyanoborohydride (2.62 g, 41.72 mmol), and the reaction mixture was stirred for 5 minutes, then more Et3N (0.18 ml, 0.1 mmol), stirred at room temperature for 4 h, then warmed to 30 °C. After 2 h, the reaction was cooled to room temperature, diluted with EtOAc and washed with brine. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure to give S1c (0.84 g, 95%). MS (ESI) m / z 388.1 [M+H] + 。

[0532] Synthesis of 7-(5-ethynylpyridin-2-yl)-9-(oxetan-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane (S1) A solution of S1c (0.84 g, 0 mol), CuI (24.73 mg, 0.13 mmol), PdCl2(tBu2PPh)2 (45.7 mg, 0.06 mmol), and trimethylsilylacetylene (0.92 ml, 0.01 mol) in a 3:1 mixture of CH3CN (9 mL) / Et3N (3 mL) was degassed with argon for 10 minutes. The reaction mixture was heated to 40 °C for a total of 90 minutes. The reaction was diluted with EtOAc and washed with NaHCO3 solution, dried over Na2SO4. Filtered and concentrated under reduced pressure. The crude residue was dissolved in MeOH (5 ml) and potassium carbonate (0.45 g, 3.0 mmol) was added, and the mixture was stirred at room temperature. After 15 minutes, the reaction was concentrated to dryness, then diluted with DCM and washed with brine. The organic extract was dried over Na2SO4 to give S1 (300 mg, 48%). MS (ESI) m / z 286.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.17 (dd, J = 2.3, 0.8 Hz, 1H), 7.40 (dd, J = 8.9, 2.3 Hz, 1H), 6.35 (dd, J = 8.9, 0.8 Hz, 1H), 4.55 (t, J = 6.2 Hz, 2H), 4.42 (t, J = 5.9 Hz, 2H), 4.25 (p, J = 6.2 Hz, 1H), 3.84 (dt, J = 11.3, 2.2 Hz, 2H), 3.78 (d, J = 12.9 Hz, 2H), 3.71 (dt, J = 11.5, 0.9 Hz, 2H), 3.24 (ddd, J = 12.9, 4.9, 2.0 Hz, 2H), 2.92 (s, 1H), 2.65 - 2.52 (m, 2H).

[0533]

[0534] Synthesis of 7-(5-ethynylpyridin-2-yl)-9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane. Preparation of the title compound S2 was carried out according to the method proposed for the synthesis of compound S1, but formaldehyde was used instead. MS (ESI) m / z 244.2 [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 8.33 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H), 4.01 (d, J = 11.2 Hz, 2H), 3.91 (d, J = 12.9 Hz, 2H), 3.85 (d, J = 11.2 Hz, 2H), 3.53 (ddd, J = 13.0, 4.8, 2.0 Hz, 2H), 3.07 (s, 1H), 2.86 - 2.75 (m, 2H), 2.62 (s, 3H).

[0535]

[0536] Synthesis of tert-butyl 3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (S3a) The title compound S3a was prepared according to the method proposed for the synthesis of compound S1a, but using tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate instead. MS (ESI) m / z 415.8 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 8.36 - 8.26 (m, 1H), 7.65 (dd, J = 9.0, 2.4 Hz, 1H), 6.40 (d, J = 9.0 Hz, 1H), 4.33 (s, 2H), 3.82 (d, J = 40.5 Hz, 2H), 3.05 (s, 2H), 1.94 (dd, J = 8.7, 4.6 Hz, 2H), 1.73 (d, J = 7.3 Hz, 2H), 1.47 (s, 9H).

[0537] Synthesis of 3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (S3b) The title compound S3b was prepared according to the method proposed for the synthesis of compound S1b, but using S3a instead. MS (ESI) m / z 316.1 [M+H] + 。

[0538] Synthesis of 3-(5-iodopyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S3c) The title compound S3c was prepared according to the method proposed for the synthesis of compound S1c, but using S3b instead. MS (ESI) m / z 372.1 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 8.22 (d, J = 2.3 Hz, 1H), 7.57 (dd, J = 8.9, 2.4 Hz, 1H), 6.30 (d, J = 9.0 Hz, 1H), 4.65 (t, J = 6.3 Hz, 2H), 4.52 (t, J = 5.8 Hz, 2H), 3.70 (dd, J = 11.8, 2.4 Hz, 2H), 3.23 - 3.08 (m, 2H), 3.04 (dd, J = 11.7, 2.2 Hz, 2H), 1.87 - 1.70 (m, 2H), 1.63 (d, J = 7.5 Hz, 2H).

[0539] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S3) The preparation of the title compound S3 was carried out according to the method proposed for the synthesis of compound S1c, but using S3c instead. MS (ESI) m / z 244.0 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.16 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.66 (d, J = 8.9 Hz, 1H), 4.76 (t, J = 6.4 Hz, 3H), 4.57 (t, J = 5.8 Hz, 3H), 3.88 (dd, J = 12.2, 2.4 Hz, 3H), 3.78 (ddd, J = 11.9, 6.5, 5.4 Hz, 1H), 3.43 (s, 1H), 3.29 (dd, J = 6.9, 1.7 Hz, 4H), 3.10 (dd, J = 11.9, 2.2 Hz, 3H), 1.93 (dd, J = 8.7, 4.4 Hz, 2H), 1.68 (t, J = 6.9 Hz, 2H).

[0540]

[0541] Synthesis of 3-(5-iodopyridin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane (S4a) The preparation of the title compound S4a was carried out according to the method proposed for the synthesis of compound S1c, but using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate instead. MS (ESI) m / z 358.0 [M+H]+.

[0542] Synthesis of 3-(5-ethynylpyridin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane (S4). The title compound S4 was prepared according to the method proposed for the synthesis of compound S1, but using S4a instead. MS (ESI) m / z 256.2 [M+H]+. 1 1H NMR (400 MHz, methanol-d4) δ 8.13 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.9, 2.3 Hz, 1H), 6.55 (d, J = 8.9 Hz, 1H), 4.65 (t, J = 6.3 Hz, 2H), 4.36 (dd, J = 6.3, 4.7 Hz, 2H), 3.77 (dd, J = 19.2, 5.7 Hz, 3H), 3.44 (s, 4H), 3.37 (s, 1H), 2.61 (dt, J = 9.1, 6.2 Hz, 1H), 1.54 (d, J = 9.1 Hz, 1H).

[0543]

[0544] Synthesis of tert-butyl ((4-(4-bromophenyl)-1H-imidazol-2-yl)methyl)(methyl)carbamate (S5a) To a solution of N-(tert-butoxycarbonyl)-N-methylglycine (4.81 g, 25.41 mmol) and 2,4'-dibromoacetophenone (6.42 g, 23.1 mmol) in MeCN (50 ml) was added Et3N 9 (3.84 ml, 0.03 mol), and the mixture was stirred for 5 minutes (slight exotherm), then warmed to 30 °C. The mixture was cooled to room temperature, diluted with EtOAc and washed with saturated NH4Cl, saturated NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was suspended in a mixture of isopropanol (10 ml) and toluene (100 ml) and ammonium acetate (37 g, 0.48 mol) was added, and the reaction was refluxed for 4 h. Cooled to room temperature, diluted with isopropyl acetate, washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by column chromatography (50% to 100% EtOAc / hexane) to give S5a (8.0 g, 90%) MS (ESI) m / z368 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.61 (d, J = 8.1 Hz, 2H), 7.54 - 7.45 (m, 2H), 7.40 (s, 1H), 4.50 (s, 2H), 2.91 (s, 3H), 1.45 (d, J = 21.0 Hz, 9H).

[0545] Synthesis of tert-butyl methyl((4-(4-((trimethylsilyl)ethynyl)phenyl)-1H-imidazol-2-yl)methyl)carbamate (S5b) A solution of S5a (8 g, 0.02 mol), CuI (0.249 g, 1.0 mmol), PdCl2(tBu2PPh)2 (0.408 g, 0.655 mmol), and trimethylsilylacetylene (12.44 ml, 0.09 mol) in a 3:1 mixture of CH3CN / Et3N (50 mL) was degassed with argon for 10 minutes. The reaction mixture was heated to 65 °C overnight. The reaction was diluted with EtOAc and washed with NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was used in the next step without purification (5.85 g, 70%). MS (ESI) m / z 384.3 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 7.66 (d, J = 8.0 Hz, 2H), 7.45 - 7.31 (m, 3H), 4.84 (s, 2H), 2.91 (s, 4H), 1.46 (s, 9H), 0.23 (s, 9H).

[0546] Synthesis of 2-(4-ethynylphenyl)-7-methyl-7,8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one (S5) To a cold solution of S5b (1450 mg, 0 mol) in 2-methyltetrahydrofuran (3 ml) was added sodium hydride (60%, 0.21 g, 0.01 mol). After 10 minutes, methyl bromoacetate (0.72 ml, 0.01 mol) was added; the mixture was stirred for 5 minutes and then warmed to room temperature. After 30 minutes, the reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (20% to 55% EtOAc / hexane). The product was dissolved in DCE (10 ml) and HCl (4.0 M in dioxane, 11.69 ml), and warmed to 25 °C. After 2 h, the reaction was concentrated in vacuo. The residue was dissolved in DMF (10 ml), cesium carbonate (3.05 g, 0.01 mol) was added, and the mixture was warmed to 65 °C for 45 minutes, cooled to room temperature, MeOH (10 mL) was added, and the mixture was stirred for 25 minutes. It was slowly diluted with ~40 mL of water and stirred for 20 minutes. The precipitated solid was filtered off and washed with 30% MeOH / water. It was concentrated under reduced pressure and the crude material was used without purification (0.479 g, 62%). MS (ESI) m / z 252.1 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 4.65 (s, 2H), 4.56 (s, 2H), 4.11 (s, 1H), 2.95 (s, 3H).

[0547]

[0548] Synthesis of (1R,4R)-2-(5-iodopyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane (S6a) The preparation of the title compound S6a was carried out according to the method proposed for the synthesis of compound S1c, but using tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead. MS (ESI) m / z 358.0 [M+H] + . 1 1H NMR (400 MHz, chloroform-d) δ 8.25 (dd, J = 2.3, 0.8 Hz, 1H), 7.61 (ddd, J = 8.8, 2.3, 0.6 Hz, 1H), 6.18 (dd, J = 8.8, 0.8 Hz, 1H), 4.71 - 4.58 (m, 3H), 4.52 (t, J = 6.1 Hz, 1H), 4.45 (t, J = 5.9 Hz, 1H), 4.05 - 3.85 (m, 1H), 3.55 (d, J = 2.4 Hz, 1H), 3.43 - 3.18 (m, 2H), 2.94 (dd, J = 9.5, 2.0 Hz, 1H), 2.83 (dd, J = 9.4, 1.4 Hz, 1H), 2.00 - 1.89 (m, 1H), 1.89 - 1.80 (m, 1H), 1.39 (t, J = 7.3 Hz, 1H).

[0549] Synthesis of (1R,4R)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane (S6) The preparation of the title compound S6 was carried out according to the method proposed for the synthesis of compound S1, but using S6a instead. MS (ESI) m / z 256.1 [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 8.13 (dd, J = 2.2, 0.9 Hz, 1H), 7.37 (dd, J = 8.7, 2.3 Hz, 1H), 6.23 - 5.98 (m, 1H), 4.54 (dt, J = 12.8, 6.5 Hz, 3H), 4.39 (t, J = 6.1 Hz, 1H), 4.32 (t, J = 5.9 Hz, 1H), 3.90 - 3.75 (m, 1H), 3.31 - 3.10 (m, 2H), 2.93 (s, 1H), 2.82 (dd, J = 9.5, 2.0 Hz, 1H), 2.73 - 2.60 (m, 1H), 1.82 (ddt, J = 9.7, 2.4, 1.2 Hz, 1H), 1.73 (ddt, J = 9.8, 2.5, 1.2 Hz, 1H).

[0550]

[0551] Synthesis of 3-(5-iodopyrimidin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S7a) The title compound S7a was prepared according to the method proposed for the synthesis of compound S1c, but using 2-chloro-5-iodopyrimidine instead. MS (ESI) m / z 373.0 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 8.37 (s, 2H), 4.71 (t, J = 6.3 Hz, 2H), 4.59 (s, 2H), 4.21 (d, J = 12.4 Hz, 2H), 3.68 (s, 1H), 3.15 (s, 4H), 1.83 (s, 2H), 1.62 (s, 2H).

[0552] Synthesis of 3-(5-ethynylpyrimidin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S7) The title compound S7 was prepared according to the method proposed for the synthesis of compound S1, but using S7a instead. MS (ESI) m / z 271.1 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 4.71 (t, J = 6.2 Hz, 2H), 4.67 - 4.46 (m, 2H), 4.40 - 4.24 (m, 2H), 3.69 (p, J = 6.1 Hz, 1H), 3.29 - 3.10 (m, 4H), 1.89 - 1.73 (m, 2H), 1.74 - 1.47 (m, 2H).

[0553]

[0554] Synthesis of (R)-8-(5-iodopyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (S8a). The title compound S8a was prepared according to the method proposed for the synthesis of compound S1a, but using (R)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride instead. MS(ESI) m / z 346.1 [M+H] + 。

[0555] Synthesis of (R)-8-(5-ethynylpyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (S8). The title compound S8 was prepared according to the method proposed for the synthesis of compound S1, but using S8a instead. MS(ESI) m / z 244.2 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.30 (dd, J = 2.3, 0.8 Hz, 1H), 7.54 (dd, J = 8.8, 2.3 Hz, 1H), 6.56 (dd, J = 8.9, 0.8 Hz, 1H), 4.23 - 4.04 (m, 2H), 3.88 (dd, J = 11.4, 3.4 Hz, 1H), 3.81 (dd, J = 11.1, 3.1 Hz, 1H), 3.73 (t, J = 11.5 Hz, 1H), 3.32 (t, J = 10.6 Hz, 1H), 3.13 - 3.01 (m, 2H), 2.86 (d, J = 11.4 Hz, 1H), 2.72 (d, J = 11.5 Hz, 1H), 2.54 (t, J = 11.7 Hz, 1H), 2.49 - 2.25 (m, 2H).

[0556]

[0557] Synthesis of (S)-8-(5-iodopyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (S9a). The title compound S9a was prepared according to the method proposed for the synthesis of compound S1a, but using (R)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride instead. MS(ESI) m / z 346.1 [M+H] + 。

[0558] Synthesis of (S)-8-(5-ethynylpyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (S9). The title compound S9 was prepared according to the method proposed for the synthesis of compound S1, but using S9a instead. MS(ESI) m / z 244.2 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 8.30 (dd, J = 2.3, 0.8 Hz, 1H), 7.54 (dd, J = 8.8, 2.3 Hz, 1H), 6.56 (dd, J = 8.9, 0.8 Hz, 1H), 4.23 - 4.04 (m, 2H), 3.88 (dd, J = 11.4, 3.4 Hz, 1H), 3.81 (dd, J = 11.1, 3.1 Hz, 1H), 3.73 (t, J = 11.5 Hz, 1H), 3.32 (t, J = 10.6 Hz, 1H), 3.13 - 3.01 (m, 2H), 2.86 (d, J = 11.4 Hz, 1H), 2.72 (d, J = 11.5 Hz, 1H), 2.54 (t, J = 11.7 Hz, 1H), 2.49 - 2.25 (m, 2H).

[0559]

[0560] 1-(5-Iodopyridin-2-yl)-4-(3-methyloxetan-3-yl)piperazine (S10a). 1-Benzyl-4-(3-methyloxetan-3-yl)piperazine (6.75 g, 27.4 mmol) in EtOH (55 ml) and palladium (10% on carbon, 1.46 g, 1.37 mmol) were combined in a PARR flask and shaken overnight at 45 PSI on a hydrogenator. The reaction was filtered through Celite, the cake was washed with 25% MeOH / DCM and the filtrate was concentrated under reduced pressure. The residue was combined with 2-fluoro-5-iodopyridine to prepare the title compound S10a according to the method proposed for the synthesis of compound S1a. MS (ESI) m / z 360.0 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 6.48 (d, J = 9.0 Hz, 1H), 4.62 (d, J = 5.5 Hz, 2H), 4.26 (d, J = 5.5 Hz, 2H), 3.54 (s, 4H), 2.44 (s, 5H), 1.37 (s, 3H).

[0561] 1-(5-Ethynylpyridin-2-yl)-4-(3-methyloxetan-3-yl)piperazine (S10). The title compound S10 was prepared according to the method proposed for the synthesis of compound S1, but using S10a instead. MS (ESI) m / z 258.0 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.18 (dd, J = 2.3, 0.8 Hz, 1H), 7.56 (dd, J = 8.9, 2.3 Hz, 1H), 6.76 (dd, J = 9.0, 0.8 Hz, 1H), 4.78 - 4.52 (m, 2H), 4.28 (d, J = 5.9 Hz, 2H), 3.65 - 3.48 (m, 4H), 3.43 (s, 1H), 2.59 - 2.39 (m, 4H), 1.38 (d, J = 0.7 Hz, 3H).

[0562]

[0563] Synthesis of 3-(5-iodopyridin-2-yl)-8-((S)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octane (S11a). A solution of S3b (1.0 g, 3.173 mmol), (R)-tetrahydrofuran-3-yl methanesulfonate (965 mg, 5.807 mmol) and potassium carbonate (1754 mg, 12.69 mmol) in CH3CN (15 mL) was heated under reflux for 48 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with brine. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0% to 5% MeOH / EtOAc) to give S11a (355.2 mg, 29%) MS (ESI) m / z 386.1 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 8.22 (dd, J = 2.3, 0.7 Hz, 1H), 7.56 (dd, J = 8.9, 2.4 Hz, 1H), 6.29 (dd, J = 9.0, 0.7 Hz, 1H), 3.96 - 3.84 (m, 2H), 3.76 (dt, J = 8.6, 7.6 Hz, 1H), 3.62 (ddd, J = 11.5, 8.9, 2.5 Hz, 2H), 3.55 (dd, J = 8.2, 6.9 Hz, 1H), 3.33 (d, J = 4.7 Hz, 1H), 3.20 (d, J = 3.4 Hz, 1H), 3.11 - 2.97 (m, 3H), 2.02 (dtd, J = 12.1, 7.4, 4.7 Hz, 1H), 1.95 - 1.87 (m, 2H), 1.87 - 1.72 (m, 1H), 1.67 - 1.56 (m, 2H).

[0564] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-((S)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octane (S11). The title compound S11 was prepared according to the method proposed for the synthesis of compound S1, but using S11a instead. MS (ESI) m / z 284.1 [M+H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.22 - 8.10 (m, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.65 (dd, J = 9.1, 0.8 Hz, 1H), 3.97 (td, J = 8.1, 4.5 Hz, 2H), 3.89 - 3.74 (m, 3H), 3.63 (dd, J = 8.4, 6.6 Hz, 1H), 3.48 (d, J = 4.4 Hz, 1H), 3.42 (s, 1H), 3.35 (s, 1H), 3.26 - 3.19 (m, 1H), 3.12 (dt, J = 12.2, 3.5 Hz, 2H), 2.15 (ddd, J = 11.8, 8.2, 4.5 Hz, 1H), 2.03 (dd, J = 14.4, 7.3 Hz, 2H), 1.85 (dq, J = 12.0, 7.8 Hz, 1H), 1.69 (d, J = 9.1 Hz, 2H).

[0565]

[0566] Synthesis of 3-(5-iodopyridin-2-yl)-8-((R)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octane (S12a). The title compound S12a was prepared according to the method proposed for the synthesis of compound S11a, but using (S)-tetrahydrofuran-3-yl methanesulfonate instead. MS (ESI) m / z 386.1 [M+H] + 。1H NMR (400 MHz, chloroform-d) δ 8.28 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 9.0, 2.4 Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 4.04 - 3.91 (m, 2H), 3.90 - 3.75 (m, 1H), 3.68 (ddd, J = 11.6, 8.8, 2.5 Hz, 2H), 3.61 (dd, J = 8.2, 6.9 Hz, 1H), 3.39 (q, J = 2.7 Hz, 1H), 3.26 (dt, J = 5.0, 2.1 Hz, 1H), 3.18 - 3.04 (m, 3H), 2.17 - 2.01 (m, 1H), 1.97 (dd, J = 9.4, 5.6 Hz, 2H), 1.90 - 1.77 (m, 1H), 1.74 - 1.63 (m, 2H).

[0567] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-((R)-tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octane (S12). The title compound S12 was prepared according to the method proposed for the synthesis of compound S1, but using S12a instead. MS (ESI) m / z 284.1 [M+H] + . 1 1H NMR (400 MHz, methanol-d4) δ 8.22 - 8.07 (m, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.65 (dd, J = 8.8, 0.9 Hz, 1H), 3.96 (td, J = 8.1, 4.5 Hz, 2H), 3.88 - 3.74 (m, 3H), 3.63 (dd, J = 8.4, 6.6 Hz, 1H), 3.48 (s, 1H), 3.42 (s, 1H), 3.35 (s, 1H), 3.24 (t, J = 7.0 Hz, 1H), 3.12 (dt, J = 12.1, 3.4 Hz, 2H), 2.26 - 2.09 (m, 1H), 2.03 (dd, J = 14.1, 7.5 Hz, 2H), 1.85 (dq, J = 12.0, 8.0 Hz, 1H), 1.69 (d, J = 9.1 Hz, 2H).

[0568]

[0569] Synthesis of 3-(5-iodopyridin-2-yl)-8-(3-methyloxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S13a) A suspension of S3b (3 g, 9.519 mmol), diethyl 2-bromo-2-methylmalonate (2.25 ml, 11.78 mmol), and sodium carbonate (1.19 g, 19.19 mmol) in NMP (30 mL) in a 100 ml sealed tube was stirred at 70 °C for 48 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed 2x with brine. The organic extract was dried over Na2SO4, filtered, and the crude residue was purified by silica gel column chromatography (10% - 20% EtOAc / hexane) to give diethyl 2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)-2-methylmalonate (2.32 g, 50%). MS (ESI) m / z 488.0 [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 8.27 (dd, J = 2.4, 0.7 Hz, 1H), 7.61 (dd, J = 9.0, 2.4 Hz, 1H), 6.51 - 6.27 (m, 1H), 4.37 - 4.07 (m, 4H), 3.84 (s, 2H), 3.79 - 3.72 (m, 2H), 3.29 - 3.07 (m, 2H), 1.77 - 1.63 (m, 4H), 1.62 (s, 3H), 1.27 (t, J = 7.2 Hz, 6H).

[0570] To a solution of diethyl 2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)-2-methylmalonate (907.9 mg, 1.863 mmol) in DCM (40 mL) was added Dibal-H (1.0 M in toluene, 93 mL) at -78 °C. The reaction was gradually warmed to room temperature and stirred overnight. Dibal-H (1.0 M in DCM, 16 mL) was added, stirred for 1 h, then cooled to 0 °C and diluted with Et2O. Water (4.4 mL), 15% NaOH (4.4 mL), and then water (10.9 mL) were added slowly, warmed to room temperature and stirred for 15 minutes. Na2SO4 was added, stirred for 15 minutes, and then the salts were filtered off to afford 2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)-2-methylpropane-1,3-diol (2.059 g, 65%). MS (ESI) m / z 404.0 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.18 (dd, J = 2.4, 0.7 Hz, 1H), 7.69 (dd, J = 9.0, 2.4 Hz, 1H), 6.54 (d, J = 9.1 Hz, 1H), 3.91 - 3.66 (m, 4H), 3.49 (s, 4H), 3.10 - 2.88 (m, 2H), 1.83 (d, J = 8.8 Hz, 2H), 1.72 (t, J = 6.6 Hz, 2H), 1.00 (s, 3H).

[0571] To a solution of 2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropane-1,3-diol (2.06 g, 5.106 mmol) and triethylamine (1.5 ml, 10.76 mmol) in THF (25 mL) at 0 °C was added methanesulfonyl chloride (0.40 ml, 5.169 mmol). The reaction was gradually warmed to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic extract was dried over Na2SO4, filtered, and the crude residue was purified by silica gel column chromatography (25%-50% EtOAc / hexane) to afford 3-chloro-2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropan-1-ol (441.6 mg, 20.5%). MS (ESI) m / z 422.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.27 (dd, J = 2.4, 0.7 Hz, 1H), 7.62 (dd, J = 8.9, 2.4 Hz, 1H), 6.35 (dd, J = 9.0, 0.7 Hz, 1H), 4.63 (s, 1H), 3.90 - 3.63 (m, 4H), 3.56 (d, J = 5.1 Hz, 1H), 3.35 (s, 1H), 3.06 (dt, J = 11.8, 3.0 Hz, 2H), 2.87 (t, J = 13.5 Hz, 1H), 2.66 (d, J = 14.0 Hz, 1H), 1.88 (dt, J = 9.9, 4.9 Hz, 2H), 1.76 - 1.63 (m, 2H), 1.57 (s, 3H).

[0572] To a solution of 3-chloro-2-(3-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropan-1-ol (418.5 mg, 0.992 mmol) in THF (10 mL) at 0 °C was added potassium tert-butoxide (1.0 M THF, 3 ml). After 10 minutes, the reaction mixture was quenched with water, diluted with EtOAc and washed with brine. The organic extract was dried over Na2SO4, filtered, and the crude residue was purified by silica gel column chromatography (50%-100% EtOAc / hexane) to afford S13a (222.8 mg, 58% yield). MS (ESI) m / z 386.1 [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 8.27 (dd, J = 2.4, 0.7 Hz, 1H), 7.61 (dd, J = 9.0, 2.4 Hz, 1H), 6.35 (dd, J = 9.0, 0.7 Hz, 1H), 3.68 (ddd, J = 11.5, 4.4, 2.6 Hz, 2H), 3.49 - 3.34 (m, 1H), 3.30 (q, J = 2.7 Hz, 1H), 3.07 (dd, J = 11.6, 2.5 Hz, 2H), 2.70 (dd, J = 5.0, 0.7 Hz, 1H), 2.64 - 2.53 (m, 2H), 2.39 (d, J = 13.2 Hz, 1H), 1.96 - 1.79 (m, 2H), 1.68 - 1.57 (m, 2H), 1.42 (d, J = 0.6 Hz, 3H).

[0573] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-(3-methyloxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S13). The title compound S13 was prepared according to the method proposed for the synthesis of compound S1, but using S13a instead. MS (ESI) m / z 284.2 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.15 (dd, J = 2.3, 0.8 Hz, 1H), 7.53 (dd, J = 8.9, 2.3 Hz, 1H), 6.64 (dd, J = 9.0, 0.8 Hz, 1H), 3.91 - 3.74 (m, 3H), 3.50 - 3.43 (m, 1H), 3.42 (s, 1H), 3.39 - 3.32 (m, 1H), 3.08 (dt, J = 11.7, 1.9 Hz, 3H), 2.72 (dd, J = 4.9, 0.7 Hz, 2H), 2.66 (d, J = 13.3 Hz, 1H), 2.60 (d, J = 4.9 Hz, 1H), 2.43 (d, J = 13.3 Hz, 1H), 1.94 (dd, J = 9.4, 5.5 Hz, 3H), 1.69 - 1.57 (m, 2H), 1.42 (d, J = 0.6 Hz, 4H).

[0574]

[0575] Synthesis of 1-(5-bromopyridin-2-yl)piperazine hydrochloride (S14a) To a solution of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (5 g, 14.61 mmol) in DCM (60 mL) and MeOH (18 mL) was added HCl (4.0 M in dioxane, 18 mL, 72 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was diluted with DCM and washed with 2N NaOH. The aqueous layer was extracted with DCM 2x and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford S14a (3.2 g, 90.4%). MS (ESI) m / z 242.1 ([M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.18 (dd, J = 2.6, 0.7 Hz, 1H), 7.52 (dd, J = 9.0, 2.6 Hz, 1H), 6.53 (dd, J = 9.1, 0.7 Hz, 1H), 3.54 - 3.40 (m, 4H), 3.09 - 2.87 (m, 4H).

[0576] Synthesis of (R)-1-(5-bromopyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S14b). The title compound S14a was prepared according to the method proposed for the synthesis of compound S11a, but using (S)-tetrahydrofuran-3-yl methanesulfonate in place of S14a. MS (ESI) m / z 312.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.19 (dd, J = 2.6, 0.7 Hz, 1H), 7.53 (dd, J = 9.0, 2.5 Hz, 1H), 6.54 (dd, J = 9.0, 0.7 Hz, 1H), 3.96 (td, J = 8.6, 4.4 Hz, 1H), 3.91 (dd, J = 8.7, 6.8 Hz, 1H), 3.80 (td, J = 8.4, 7.5 Hz, 1H), 3.69 (t, J = 7.7 Hz, 1H), 3.52 (t, J = 5.3 Hz, 4H), 3.01 (t, J = 7.3 Hz, 1H), 2.63 (d, J = 9.9 Hz, 2H), 2.57 - 2.46 (m, 2H), 2.07 (ddd, J = 9.9, 7.1, 3.3 Hz, 1H), 1.90 (q, J = 11.1, 9.5 Hz, 1H).

[0577] Synthesis of (R)-1-(5-ethynylpyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S14). The title compound S14 was prepared according to the method proposed for the synthesis of compound S1, but using S14b in place of S14a. MS (ESI) m / z 258.1 [M+H]+ . 1 H NMR (400 MHz, methanol-d4) δ 8.18 (d, J = 2.3 Hz, 1H), 7.56 (dd, J = 8.8, 2.3 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 3.95 (dt, J = 8.5, 4.3 Hz, 1H), 3.90 (dd, J = 8.8, 7.0 Hz, 2H), 3.76 (q, J = 8.2 Hz, 1H), 3.68 (dd, J = 8.8, 6.6 Hz, 1H), 3.58 (t, J = 5.2 Hz, 4H), 3.43 (s, 1H), 3.09 - 2.97 (m, 1H), 2.65 (dt, J = 10.6, 5.2 Hz, 2H), 2.54 (dt, J = 11.2, 5.2 Hz, 2H), 2.20 - 2.06 (m, 1H), 1.96 - 1.83 (m, 1H).

[0578]

[0579] Synthesis of (S)-1-(5-bromopyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S15a). The title compound S15a was prepared according to the method proposed for the synthesis of compound S11a, but using S14a in place. MS (ESI) m / z 312.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.18 (dd, J = 2.6, 0.7 Hz, 1H), 7.52 (dd, J = 9.0, 2.6 Hz, 1H), 6.53 (dd, J = 9.1, 0.7 Hz, 1H), 3.96 (td, J = 8.6, 4.4 Hz, 1H), 3.91 (dd, J = 8.6, 6.8 Hz, 1H), 3.80 (td, J = 8.4, 7.5 Hz, 1H), 3.68 (dd, J = 8.7, 6.7 Hz, 1H), 3.52 (dd, J = 5.9, 4.5 Hz, 4H), 3.00 (p, J = 7.1 Hz, 1H), 2.63 (dt, J = 10.7, 5.2 Hz, 2H), 2.50 (dt, J = 10.8, 5.1 Hz, 2H), 2.17 - 1.99 (m, 1H), 1.99 - 1.79 (m, 1H).

[0580] Synthesis of (S)-1-(5-ethynylpyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S15). The title compound S15 was prepared according to the method proposed for the synthesis of compound S1, but using S15a in place. MS (ESI) m / z 258.1 [M+H] + . 11H NMR (400 MHz, methanol-d4) δ 8.09 (dd, J = 2.4, 0.8 Hz, 1H), 7.47 (dd, J = 8.9, 2.3 Hz, 1H), 6.66 (dd, J = 9.0, 0.8 Hz, 1H), 3.86 (dt, J = 8.6, 4.3 Hz, 1H), 3.80 (dd, J = 8.9, 7.0 Hz, 2H), 3.67 (td, J = 8.4, 7.2 Hz, 1H), 3.59 (dd, J = 8.7, 6.6 Hz, 1H), 3.49 (t, J = 5.2 Hz, 4H), 3.34 (s, 1H), 3.02 - 2.86 (m, 1H), 2.55 (dt, J = 10.7, 5.2 Hz, 2H), 2.44 (dt, J = 11.1, 5.2 Hz, 2H), 2.10 - 1.94 (m, 2H), 1.86 - 1.71 (m, 2H).

[0581]

[0582] Synthesis of tert-butyl 3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (S16). The title compound S16 was prepared according to the method proposed for the synthesis of compound S1, but using S3a instead. MS (ESI) m / z 313.9 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.18 (dd, J = 2.3, 0.8 Hz, 1H), 7.56 (dd, J = 8.9, 2.3 Hz, 1H), 6.69 (dd, J = 8.9, 0.9 Hz, 1H), 4.45 - 4.30 (m, 2H), 4.04 - 3.95 (m, 2H), 3.43 (s, 1H), 3.02 (d, J = 12.2 Hz, 2H), 1.94 (dd, J = 8.7, 4.4 Hz, 2H), 1.75 (d, J = 7.3 Hz, 2H), 1.48 (s, 9H).

[0583]

[0584] Synthesis of tert-butyl 6-(5-iodopyridin-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (S17a).

[0585] The title compound S17a was prepared according to the method proposed for the synthesis of compound S1a, but using tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate instead. MS (ESI) m / z 401.9 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 8.28 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 6.14 (d, J = 8.7 Hz, 1H), 4.13 (s, 4H), 4.10 (s, 4H), 1.44 (s, 9H).

[0586] Synthesis of 6-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-2-azaspiro[3.3]heptane (S17b).

[0587] A solution of S17a (1.048 mg, 2.612 mmol), CuI (0.111 g, 0.583 mmol), PdCl2(tBu2PPh)2 (0.163 g, 0.261 mmol), TMSA (2.1 ml, 14.75 mmol), and Et3N (2.7 ml, 19.48 mmol) in CH3CN (20 mL) was degassed with argon at 0 °C for 10 minutes. The reaction mixture was stirred overnight under reflux, then cooled to room temperature, diluted with EtOAc, washed with NaHCO3 solution, dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20% to 40% EtOAc / Hex) to give the desired product (760 mg, 78%). This product (0.4 g, 1076.58 μmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1000 μl, 13.07 mmol) was added. The mixture was stirred at 0 °C. After 4 h, the reaction mixture was concentrated under reduced pressure, diluted with toluene (5 mL), and concentrated to give S17b (0.54 g, 100.1%). MS (ESI) m / z 272.1 [M+H] + 。

[0588] Synthesis of 6-(5-ethynylpyridin-2-yl)-2-(oxetan-3-yl)-2-azaspiro[3.3]heptane (S17)

[0589] To a suspension of S17b (538 mg, 1.08 mmol) and triethylamine (0.3 mL, 2.154 mmol) in 2-Me THF (4 mL) and AcOH (0.2 mL) was added oxetan-3-one (234 mg, 3.247 mmol) in 2-Me-THF (1 mL), followed by sodium cyanoborohydride (209 mg, 3.326 mmol). The reaction was stirred at room temperature. After 18 h, the reaction mixture was quenched with NaHCO3 solution and partitioned with EtOAc. The organic extract was dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (50% to 75% EtOAc / Hex). The product was dissolved in MeOH (5 mL), potassium carbonate (0.28 g, 2.05 mmol) was added and the mixture was stirred at room temperature. After 48 h, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol (2.0 mL) and sodium hydroxide solution (2 M, 2 mL) was added, and the mixture was heated to 70 °C for 18 h. The reaction was cooled to room temperature and concentrated under reduced pressure; the residue was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford S17 MS (ESI) m / z 256.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.09 (dd, J = 2.2, 0.8 Hz, 1H), 7.55 (dd, J = 8.7, 2.2 Hz, 1H), 6.36 (dd, J = 8.7, 0.8 Hz, 1H), 4.72 (td, J = 6.7, 0.5 Hz, 3H), 4.45 (ddd, J = 6.8, 4.9, 0.6 Hz, 3H), 4.13 (s, 5H), 3.76 (tt, J = 6.5, 4.9 Hz, 1H), 3.50 (s, 5H), 3.44 (s, 1H).

[0590]

[0591] Synthesis of tert-butyl (3aR,6aS)-5-(5-iodopyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (S18a) The title compound S18a was prepared according to the method described for the synthesis of compound S1a, but using (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate MS (ESI) m / z 415.8 [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 8.28 (dd, J = 2.4, 0.8 Hz, 1H), 7.63 (dd, J = 8.9, 2.3 Hz, 1H), 6.19 (d, J = 8.9 Hz, 1H), 3.66 (dd, J = 10.7, 7.0 Hz, 4H), 3.51 - 3.17 (m, 4H), 2.99 (d, J = 5.9 Hz, 2H), 1.45 (s, 9H).

[0592] Synthesis of (3aR,6aS)-2-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole (S18b). A solution of S18a (0.986 g, 2.374 mmol), CuI (0.099 g, 0.522 mmol), PdCl2(tBu2PPh)2 (0.148 g, 0.237 mmol), TMSA (1.9 ml, 13.35 mmol), and Et3N (2.5 ml, 18.04 mmol) in CH3CN (8 mL) was degassed with argon for 10 minutes. The reaction mixture was heated to 60 °C and stirred overnight. The reaction was diluted with EtOAc and washed with NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% to 30% EtOAc / Hex). The product (0.68 g, 1.75 mmol) was dissolved in a mixture of DCM (8 mL) and MeOH (2 mL), and HCl (4.0 M in dioxane, 2 ml) was added. The reaction was stirred for 18 h, diluted with DCM, and washed with 2N NaOH solution. The aqueous layer was extracted again with DCM, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give S18b (0.56 g, 112.7%). MS (ESI) m / z 286.2 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 7.82 (dd, J = 2.1, 0.7 Hz, 1H), 7.73 (dd, J = 9.5, 2.1 Hz, 1H), 6.88 (dd, J = 9.5, 0.9 Hz, 1H), 3.78 - 3.63 (m, 2H), 3.59 - 3.48 (m, 2H), 3.46 - 3.34 (m, 3H), 3.25 - 3.10 (m, 3H), -0.00 (s, 9H).

[0593] Synthesis of (3aR,6aS)-2-(5-ethynylpyridin-2-yl)-5-methyloctahydropyrrolo[3,4-c]pyrrole (S18). To a solution of S18b (0.25 g, 0.701 mmol) in DCE (6 mL) was added formaldehyde solution (0.30 mL, 8.143 mmol) and acetic acid (0.025 mL, 4.367 mmol). The reaction mixture was heated at 60 °C for 30 minutes. It was cooled to room temperature and sodium cyanoborohydride (165.1 mg, 2.63 mmol) was added. The reaction was heated at 60 °C for 45 minutes, then cooled to room temperature, diluted with EtOAc, washed with brine, the aqueous layer was back-extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and potassium carbonate (0.29 g, 2.1 mmol) was added. The reaction mixture was stirred at room temperature. After 18 h, the reaction was concentrated under reduced pressure and the residue was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give S18 (0.15 g, 87%). MS (ESI) m / z 228.1 [M+H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.19 (dd, J = 2.3, 0.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.3 Hz, 1H), 6.58 (dd, J = 8.9, 0.8 Hz, 1H), 3.70 - 3.59 (m, 1H), 3.54 - 3.45 (m, 3H), 3.10 (s, 3H), 2.97 - 2.84 (m, 2H), 2.54 (dd, J = 9.7, 4.0 Hz, 2H), 2.39 (s, 3H).

[0594]

[0595] Synthesis of (3aR,6aS)-2-(5-iodopyridin-2-yl)-5-(oxetan-3-yl)octahydropyrrolo[3,4-c]pyrrole (S19a) The title compound S19a was prepared according to the method described for the synthesis of compound S1c, but using S18a instead. MS (ESI) m / z 372.1 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.17 (dd, J = 2.3, 0.7 Hz, 1H), 7.71 (ddd, J = 8.9, 2.3, 0.8 Hz, 1H), 6.43 (dd, J = 9.0, 0.7 Hz, 1H), 4.69 (t, J = 6.6 Hz, 2H), 4.64 - 4.55 (m, 2H), 3.70 - 3.60 (m, 1H), 3.59 - 3.49 (m, 2H), 3.38 (dd, J = 10.8, 3.1 Hz, 2H), 3.02 (td, J = 7.3, 3.7 Hz, 2H), 2.88 - 2.71 (m, 2H), 2.42 (dd, J = 9.4, 4.0 Hz, 2H).

[0596] Synthesis of (3aR,6aS)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)octahydropyrrolo[3,4-c]pyrrole (S19). The title compound S19 was prepared according to the method proposed for the synthesis of compound S1, but using S19a instead. MS (ESI) m / z 270.2 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.05 (dd, J = 2.2, 0.8 Hz, 1H), 7.46 (dd, J = 8.8, 2.3 Hz, 1H), 6.43 (dd, J = 8.9, 0.8 Hz, 1H), 4.68 - 4.58 (m, 2H), 4.59 - 4.44 (m, 2H), 3.64 - 3.45 (m, 2H), 3.40 - 3.30 (m, 4H), 2.95 (dq, J = 7.5, 3.9 Hz, 2H), 2.70 (dd, J = 9.6, 7.1 Hz, 1H), 2.36 (dd, J = 9.5, 4.0 Hz, 2H).

[0597]

[0598] Synthesis of 3-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (S20a). The title compound S20a was prepared according to the method proposed for the synthesis of compound S19a, but using S3a instead. MS (ESI) m / z 286.1 [M+H] + 。

[0599] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (S20) To a solution of S20a (0.2 g, 0.7 mmol) in THF (6 mL) was added formaldehyde solution (0.13 mL, 3.5 mmol) and acetic acid (0.03 mL, 0.51 mmol). The reaction mixture was stirred overnight at room temperature. Sodium cyanoborohydride (132.09 mg, 2.1 mmol) was added. After 5 h, MeOH (2 mL) and NaOH (2 N, 2 mL) were added and the mixture was stirred for an additional 18 h. The reaction was concentrated under reduced pressure, diluted with EtOAc, washed with brine, the aqueous layer was back-extracted with EtOAc, dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (100% EtOAc to 5%-10% MeOH / EtOAc) to afford S20 (62.6 mg, 39.3%). MS (ESI) m / z 228.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.16 (dd, J = 2.4, 0.8 Hz, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.66 (dd, J = 8.9, 0.9 Hz, 1H), 3.86 (dd, J = 12.5, 2.4 Hz, 3H), 3.42 (s, 1H), 3.08 (dd, J = 12.3, 2.3 Hz, 3H), 2.36 (d, J = 2.4 Hz, 3H), 2.07 (dt, J = 7.1, 3.2 Hz, 2H), 1.68 (t, J = 6.8 Hz, 2H).

[0600]

[0601] Synthesis of 8-ethyl-3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S21) To a solution of S20a (0.24 g, 0.83 mmol) in THF (5 mL) and MeOH (2 mL) were added acetaldehyde (0.5 ml, 8.90 mmol) and acetic acid (0.04 ml, 0.7 mmol). After 18 h, sodium cyanoborohydride (314 mg, 5.0 mmol) was added. The mixture was stirred overnight, diluted with EtOAc, washed with brine, the aqueous layer was back-extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-20% MeOH / EtOAc) to give the product (0.12 g, 0.39 mmol), which was dissolved in MeOH (5 mL) and potassium carbonate (0.16 g, 1.17 mmol) was added. The reaction mixture was stirred at room temperature. After 3 h, the reaction was concentrated under reduced pressure, and the residue was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give S21 (0.09 g, 44%). MS (ESI) m / z 242.2 [M+H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.16 (dd, J = 2.3, 0.8 Hz, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.65 (dd, J = 8.9, 0.9 Hz, 1H), 3.85 (dd, J = 12.5, 2.4 Hz, 2H), 3.44 (dd, J = 4.6, 2.5 Hz, 2H), 3.41 (s, 1H), 3.09 (dd, J = 12.2, 2.2 Hz, 2H), 2.52 (q, J = 7.2 Hz, 2H), 2.00 (dt, J = 7.0, 3.1 Hz, 2H), 1.67 (t, J = 6.8 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H).

[0602]

[0603] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-isopropyl-3,8-diazabicyclo[3.2.1]octane (S22) Sodium acetate (28.74 mg, 0.35 mmol), acetic acid (21.04 mg, 0.35 mmol) and acetone (20.35 mg, 0.35 mmol) were added to a solution of S20a (0.1 g, 0.35 mmol) in methanol (1.2 ml). The mixture was stirred at 40 °C. After 1 h, sodium cyanoborohydride (44.03 mg, 0.7 mmol) was added and the reaction was stirred at 40 °C. After 12 h, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with EtOAc, washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure, and purified by silica gel column chromatography (2% MeOH / EtOAc). The product was dissolved in methanol (1 ml), potassium carbonate (0.05 g, 0.35 mmol) was added and the mixture was concentrated after 1 h, diluted with EtOAc, washed with water, dried over Na2SO4, filtered, and concentrated to give S22 (28 mg, 31.3%). MS (ESI) m / z 256.2 [M+H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.18 (d, J = 2.3 Hz, 1H), 7.57 (dd, J = 8.9, 2.4 Hz, 1H), 6.68 (d, J = 8.9 Hz, 1H), 3.93–3.68 (m, 6H), 3.43 (s, 1H), 3.23–3.12 (m, 3H), 2.86 (s, 2H), 2.07–1.92 (m, 3H), 1.75 (t, J = 6.6 Hz, 3H), 1.20 (d, J = 6.4 Hz, 8H).

[0604]

[0605] Synthesis of (2S,6R)-4-(5-iodopyridin-2-yl)-2,6-dimethylmorpholine (S23a) The title compound S23a was prepared according to the method described for the synthesis of compound S1a, but using (2S,6R)-2,6-dimethylmorpholine instead. MS (ESI) m / z 319.0 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.32 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 6.49 (d, J = 9.0 Hz, 1H), 4.00 (d, J = 12.6 Hz, 2H), 3.70 (ddd, J = 10.6, 6.3, 2.6 Hz, 2H), 2.53 (t, J = 11.6 Hz, 2H), 1.26 (d, J = 6.2 Hz, 6H).

[0606] Synthesis of (2S,6R)-4-(5-ethynylpyridin-2-yl)-2,6-dimethylmorpholine (S23) The title compound S23 was prepared according to the method proposed for the synthesis of compound S1, but using S23a instead. MS (ESI) m / z 217.1 [M+H] + 。

[0607]

[0608] Synthesis of 3-(5-ethynylpyridin-2-yl)-N,N-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxamide (S24) To a solution of S20a (200 mg, 0.558 mmol) and Et3N (0.3 ml, 2.164 mmol) in DCM (5 mL) at 0 °C was added dimethylcarbamoyl chloride (0.055 ml, 0.601 mmol). The reaction was gradually warmed to room temperature and stirred overnight. The reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and K2CO3 (313 mg, 2.236 mmol) was added. After stirring at room temperature for 48 h, the reaction was concentrated, then diluted with EtOAc and washed with brine. The organic extract was dried over Na2SO4 to give S24 (123.9 mg, 78%). MS (ESI) m / z 276.2 [M+H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.17 (dd, J = 2.3, 0.8 Hz, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.69 (dd, J = 9.0, 0.8 Hz, 1H), 4.19 (dd, J = 4.5, 2.2 Hz, 3H), 3.98 (dd, J = 12.4, 2.5 Hz, 3H), 3.42 (s, 1H), 3.11 (dd, J = 12.2, 2.1 Hz, 3H), 2.94 (s, 8H), 1.88 (dd, J = 8.5, 4.4 Hz, 3H), 1.71 (q, J = 6.7 Hz, 2H).

[0609]

[0610] Synthesis of (3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)((S)-tetrahydrofuran-2-yl)methanone (S25) To S20a suspended in CH2Cl2 (10 mL) was added (S)-tetrahydrofuran-2-carboxylic acid (0.12 mL, 1 mmol), Et3N (0.68 mL, 5 mmol), and then HATU (0.48 g, 1 mmol). The mixture was stirred for 1.5 h. The mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in MeOH (20 mL), cooled to 5 °C and potassium carbonate (0.4 g, 3 mmol) was added. After 30 minutes, the reaction was quenched with water and brine, extracted into DCM, dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (60%-100% EtOAc / hexane to 5% MeOH / EtOAc) to afford S25 (0.23 g, 74.3%). MS (ESI) m / z 312.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.29 (dd, J = 2.3, 0.8 Hz, 1H), 7.54 (dt, J = 8.9, 2.4 Hz, 1H), 6.48 (d, J = 8.8 Hz, 1H), 4.84 (t, J = 8.6 Hz, 1H), 4.66 (d, J = 6.8 Hz, 1H), 4.56 (ddd, J = 14.9, 7.4, 5.7 Hz, 2H), 4.12 (ddd, J = 20.9, 12.7, 2.3 Hz, 1H), 3.99 - 3.73 (m, 4H), 3.21 (dd, J = 12.1, 2.3 Hz, 1H), 3.14 (dd, J = 12.0, 2.4 Hz, 1H), 3.07 (s, 1H), 3.06 - 3.02 (m, 0H), 2.41 - 2.21 (m, 1H), 2.15 - 1.70 (m, 5H).

[0611]

[0612] Synthesis of tert-butyl 8-(5-iodopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (S26a) The title compound S26a was prepared according to the method proposed for the synthesis of compound S1a, but using tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate instead. MS (ESI) m / z 415.8 [M+H] + . 11H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 2.2 Hz, 1H), 7.70 (s, 1H), 6.46 (s, 1H), 4.45 (s, 2H), 3.78 (d, J = 52.7 Hz, 2H), 3.14 (dd, J = 50.9, 12.9 Hz, 2H), 2.06–1.77 (m, 4H), 1.45 (s, 12H).

[0613] Synthesis of 8-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S26b). The title compound S26b was prepared according to the method proposed for the synthesis of compound S17b, but using S26a instead. MS (ESI) m / z 286.2 [M+H] + 。

[0614] Synthesis of 8-(5-ethynylpyridin-2-yl)-3-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S26). The title compound S26 was prepared according to the method proposed for the synthesis of compound S18, but using oxetan-3-one instead. MS (ESI) m / z 270.2 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.18 (d, J = 2.3 Hz, 1H), 7.58 (dd, J = 8.8, 2.3 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.61 (dt, J = 11.1, 5.5 Hz, 7H), 3.51 - 3.44 (m, 2H), 2.64 (dd, J = 10.9, 2.6 Hz, 3H), 2.23 (d, J = 10.7 Hz, 2H), 2.14 (t, J = 6.2 Hz, 2H), 1.99 (dd, J = 8.3, 4.2 Hz, 2H).

[0615]

[0616] Synthesis of 5-iodo-2-(2-oxaspiro[3.3]heptan-6-yl)pyridine (S27a). The title compound S27a was prepared according to the method proposed for the synthesis of compound S1a, but using 2-oxa-6-azaspiro[3.3]heptane instead. 1 1H NMR (400 MHz, chloroform-d) δ 8.16 (dd, J = 2.4, 0.7 Hz, 1H), 7.52 (dd, J = 8.8, 2.4 Hz, 1H), 6.20 (d, J = 8.8 Hz, 1H), 4.84 (s, 4H), 4.17 (s, 5H).

[0617] Synthesis of 5-ethynyl-2-(2-oxaspiro[3.3]heptan-6-yl)pyridine (S27). The title compound S27 was prepared according to the method proposed for the synthesis of compound S1, but using S27a instead. MS (ESI) m / z 201.1 [M+H] + 。

[0618]

[0619] Synthesis of 7-(5-ethynylpyridin-2-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane (S28). The title compound S28 was prepared according to the method proposed for the synthesis of compound S1, but using S1b instead. MS (ESI) m / z 230.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.25 (s, 1H), 7.56 - 7.43 (m, 1H), 6.48 (d, J = 8.9 Hz, 1H), 4.42 (d, J = 13.5 Hz, 2H), 4.12 (d, J = 12.1 Hz, 2H), 3.93 (d, J = 12.2 Hz, 2H), 3.59 (d, J = 13.6 Hz, 2H), 3.36 (s, 2H), 3.00 (d, J = 1.1 Hz, 1H).

[0620]

[0621] Synthesis of (1R,4R)-2-(5-iodopyrimidin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane (S29a). The title compound S29a was prepared according to the method proposed for the synthesis of compound S7a, but using tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead. MS (ESI) m / z 359.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.37 (s, 2H), 4.79 (s, 1H), 4.69 (dt, J = 10.0, 6.5 Hz, 2H), 4.55 (t, J = 6.1 Hz, 1H), 4.48 (t, J = 5.9 Hz, 1H), 3.98 (p, J = 6.3 Hz, 1H), 3.57 (s, 1H), 3.46 (dd, J = 11.0, 1.6 Hz, 1H), 3.36 (dd, J = 10.8, 2.0 Hz, 1H), 2.98 (dd, J = 9.6, 2.0 Hz, 1H), 2.82 (d, J = 9.6 Hz, 1H), 1.97 (d, J = 9.9 Hz, 1H), 1.86 (d, J = 9.8 Hz, 1H).

[0622] Synthesis of (1R,4R)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane (S29) The preparation of the title compound S29 was carried out according to the method proposed for the synthesis of compound S1, but using S29a instead. MS(ESI) m / z 257.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.39 (s, 2H), 4.88 (s, 1H), 4.70 (dt, J = 9.5, 6.5 Hz, 2H), 4.52 (dt, J = 26.3, 6.0 Hz, 2H), 3.99 (p, J = 6.3 Hz, 1H), 3.58 (s, 1H), 3.52 (d, J = 10.9 Hz, 1H), 3.41 (dd, J = 11.0, 2.0 Hz, 1H), 3.18 (s, 1H), 2.99 (d, J = 9.6 Hz, 1H), 2.83 (d, J = 9.6 Hz, 1H), 1.98 (d, J = 9.9 Hz, 1H), 1.87 (d, J = 9.8 Hz, 1H).

[0623]

[0624] Synthesis of (1S,4S)-2-(5-iodopyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane (S30a) The preparation of the title compound S30a was carried out according to the method proposed for the synthesis of compound S1c, but using tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead. MS(ESI) m / z 358.0 [M+H] + .

[0625] Synthesis of (1S,4S)-2-(5-ethynylpyridin-2-yl)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane (S30) The preparation of the title compound S30 was carried out according to the method proposed for the synthesis of compound S1, but using S30a instead. MS(ESI) m / z 256.2 ([M+H] + . 11H NMR (400 MHz, chloroform-d) δ 8.12 (dd, J = 2.3, 0.8 Hz, 1H), 7.36 (dd, J = 8.7, 2.3 Hz, 1H), 6.11 (d, J = 8.7 Hz, 1H), 4.59 (s, 1H), 4.53 (dt, J = 12.9, 6.5 Hz, 2H), 4.36 (dt, J = 31.2, 5.3 Hz, 2H), 3.82 (p, J = 5.9 Hz, 1H), 3.44 (s, 1H), 3.17 (s, 1H), 2.91 (s, 1H), 2.87 - 2.73 (m, 1H), 2.75 - 2.64 (m, 1H), 1.94 - 1.78 (m, 1H), 1.73 (d, J = 9.7 Hz, 1H).

[0626]

[0627] Synthesis of 8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane 2,2,2-trifluoroacetate (S31a). The title compound S31a was prepared according to the method proposed for the synthesis of compound S1c, but tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate was used instead, and then Boc deprotection was carried out in the same manner as for the synthesis of compound S17b. MS (ESI) m / z 169.2 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 4.79 (t, J = 6.9 Hz, 2H), 4.66 (dd, J = 7.2, 5.2 Hz, 2H), 4.10 (tt, J = 6.8, 5.2 Hz, 1H), 3.76 (dq, J = 5.0, 2.3 Hz, 2H), 3.51 (dd, J = 13.6, 2.0 Hz, 2H), 3.41 - 3.33 (m, 2H), 2.31 - 2.21 (m, 2H), 2.11 - 1.95 (m, 2H).

[0628] Synthesis of 2-chloro-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-1,5-naphthyridine (S31b). The title compound S31b was prepared according to the method proposed for the synthesis of compound S1a, but 2,6-dichloro-1,5-naphthyridine was used instead. MS (ESI) m / z 330.7 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 7.95 (dd, J = 9.5, 0.8 Hz, 1H), 7.86 (dd, J = 8.8, 0.8 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 9.4 Hz, 1H), 4.71 (t, J = 6.2 Hz, 2H), 4.58 (t, J = 5.7 Hz, 2H), 4.05 (d, J = 11.3 Hz, 2H), 3.74 - 3.63 (m, 1H), 3.28 - 3.20 (m, 5H), 1.86 (dd, J = 9.1, 4.4 Hz, 2H).

[0629] Synthesis of 2-ethynyl-6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-1,5-naphthyridine (S31). The title compound S31 was prepared according to the method proposed for the synthesis of compound S1, but using S31b instead. MS (ESI) m / z 321.2 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 7.93 (d, J = 9.5 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 9.5 Hz, 1H), 4.63 (t, J = 6.2 Hz, 2H), 4.50 (t, J = 5.8 Hz, 2H), 4.01 (d, J = 11.8 Hz, 2H), 3.61 (p, J = 6.0 Hz, 1H), 3.27 - 3.07 (m, 4H), 3.06 (s, 1H), 1.77 (dd, J = 8.9, 4.3 Hz, 2H), 1.66 - 1.52 (m, 2H).

[0630]

[0631] Synthesis of 3,3'-(6-chloro-1,3,5-triazine-2,4-diyl)bis(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane) (S32a) The title compound S32a was prepared according to the method proposed for the synthesis of compound S1a, but using S31a and 2,4,6-trichloro-1,3,5-triazine instead. MS (ESI) m / z 448.3 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 4.70 (t, J = 6.2 Hz, 4H), 4.56 (s, 3H), 4.32 (d, J = 13.0 Hz, 2H), 4.30 - 4.20 (m, 2H), 3.64 (h, J = 5.8 Hz, 2H), 3.21 - 3.04 (m, 8H), 1.89 - 1.73 (m, 4H), 1.71 - 1.51 (m, 5H).

[0632] Synthesis of 3,3'-(6-ethynyl-1,3,5-triazine-2,4-diyl)bis(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane) (S32). The title compound S32 was prepared according to the method proposed for the synthesis of compound S1, but using S32a instead. MS (ESI) m / z 438.3 [M+H] + . 1 1H NMR (400 MHz, chloroform-d) δ 4.55 (t, J = 6.2 Hz, 4H), 4.48 - 4.33 (m, 4H), 4.23 (d, J = 12.5 Hz, 2H), 4.12 (t, J = 10.9 Hz, 2H), 3.49 (q, J = 5.7 Hz, 2H), 3.05 - 2.85 (m, 8H), 2.78 (s, 1H), 1.71 - 1.57 (m, 4H), 1.52 - 1.34 (m, 4H).

[0633]

[0634] Synthesis of 3-(5-chloropyrazin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S33a) The title compound S33a was prepared according to the method proposed for the synthesis of compound S1c, but using 2,5-dichloropyrazine instead. MS (ESI) m / z 281.3 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 1.4 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 4.72 (t, J = 6.3 Hz, 2H), 4.58 (t, J = 5.8 Hz, 2H), 3.77 (dd, J = 11.6, 2.3 Hz, 2H), 3.69 (ddd, J = 11.9, 6.5, 5.5 Hz, 1H), 3.23 (dd, J = 4.8, 2.6 Hz, 2H), 3.18 (dd, J = 11.5, 2.3 Hz, 2H), 1.92 - 1.83 (m, 2H), 1.73 - 1.65 (m, 2H).

[0635] Synthesis of 3-(5-ethynylpyrazin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S33) The preparation of the title compound S33 was carried out according to the method proposed for the synthesis of compound S1, but using S33a instead. MS(ESI) m / z 271.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.21 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 4.73 (dd, J = 6.3 Hz, 2H), 4.59 (t, J = 5.8 Hz, 2H), 3.90 (d, J = 10.5 Hz, 1H), 3.70 (p, J = 6.0 Hz, 1H), 3.27 - 3.18 (m, 4H), 3.17 (s, 1H), 1.94 - 1.83 (m, 2H), 1.74 - 1.64 (m, 2H), 1.57 (s, 1H).

[0636]

[0637] Synthesis of tert-butyl 6-(5-iodopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (S34a) The preparation of the title compound S34a was carried out according to the method proposed for the synthesis of compound S1a, but using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate instead. MS(ESI) m / z 401.8 [M+H] + 。

[0638] Synthesis of 6-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (S34b). The preparation of the title compound S34b was carried out according to the method proposed for the synthesis of compound S1c, but using S34a instead. MS(ESI) m / z 272.2 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.22 - 8.09 (m, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 5.87 (d, J = 2.8 Hz, 1H), 5.47 (d, J = 2.7 Hz, 1H), 4.86 - 4.71 (m, 3H), 3.69 - 3.57 (m, 3H), 3.53 - 3.44 (m, 3H), 3.10 - 3.03 (m, 3H), 2.96 (d, J = 9.0 Hz, 2H), 2.02 - 1.95 (m, 1H), 0.00 (s, 9H).

[0639] Synthesis of 6-(5-ethynylpyridin-2-yl)-3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane (S34). The title compound S34 was prepared according to the method proposed for the synthesis of compound S1, but using S34b instead. MS (ESI) m / z 256.1 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 8.32 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 6.26 (d, J = 8.6 Hz, 1H), 4.56 (t, J = 6.8 Hz, 2H), 4.51 - 4.32 (m, 4H), 3.73 (s, 1H), 3.26 - 3.11 (m, 2H), 3.08 (s, 1H), 3.00 - 2.85 (m, 2H), 2.71 - 2.58 (m, 1H), 2.21 - 1.98 (m, 1H).

[0640]

[0641] Synthesis of tert-butyl 3-(4-iodophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (S35a). The title compound S35aa was prepared according to the method proposed for the synthesis of compound S1c, but using 1,4-diiodobenzene instead. MS (ESI) m / z 414.9 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 7.56 - 7.43 (m, 2H), 6.68 - 6.55 (m, 2H), 4.34 (s, 2H), 3.35 (dd, J = 11.2, 2.4 Hz, 2H), 2.97 (s, 2H), 2.00 - 1.80 (m, 4H), 1.46 (s, 9H).

[0642] Synthesis of 3-(4-iodophenyl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S35b). The title compound S35b was prepared according to the method proposed for the synthesis of compound S1c, but using S35a instead. MS (ESI) m / z 371.2 [M+H] + 。

[0643] Synthesis of 3-(4-ethynylphenyl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S35). The title compound S35 was prepared according to the method proposed for the synthesis of compound S1, but using S35b instead. MS (ESI) m / z 269.2 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 7.19 - 7.08 (m, 2H), 6.53 - 6.40 (m, 2H), 4.49 (t, J = 6.3 Hz, 2H), 4.36 (s, 2H), 3.50 (s, 1H), 3.18 (dd, J = 11.0, 2.5 Hz, 2H), 3.00 (s, 2H), 2.84 (d, J = 10.7 Hz, 2H), 2.75 (s, 1H), 1.72 - 1.47 (m, 4H).

[0644]

[0645] Synthesis of tert-butyl 3-(5-iodopyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (S36a). The title compound S36a was prepared according to the method proposed for the synthesis of compound S1a, but using 2-chloro-5-iodopyrimidine instead. MS (ESI) m / z 416.8 [M+H] + 。

[0646] Synthesis of 3-(5-ethynylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S36). The title compound S36 was prepared according to the method proposed for the synthesis of compound S1, but using S36a instead. MS (ESI) m / z 215.2 [M+H] + 。

[0647]

[0648] Synthesis of 3-(5-iodopyridin-2-yl)-1,5-dimethyl-7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1]nonan-9-one (S37a). The title compound S37a was prepared according to the method proposed for the synthesis of compound S1c, but 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one was used instead. MS (ESI) m / z 428.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.34 (s, 1H), 7.71 (s, 1H), 6.62 (s, 1H), 4.70 (s, 2H), 4.37 (t, J = 6.5 Hz, 2H), 4.15 (t, J = 6.4 Hz, 3H), 3.29 - 3.05 (m, 3H), 3.02 - 2.80 (m, 1H), 2.17 (dd, J = 11.2, 2.3 Hz, 2H), 1.55 (s, 2H), 1.03 (s, 6H).

[0649] Synthesis of 3-(5-ethynylpyridin-2-yl)-1,5-dimethyl-7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1]nonan-9-one (S37) The title compound S37 was prepared according to the method proposed for the synthesis of compound S1, but S37a was used instead. MS (ESI) m / z 326.3 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.34 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.9 Hz, 1H), 4.80 (d, J = 13.4 Hz, 2H), 4.34 (t, J = 6.4 Hz, 2H), 4.12 (t, J = 6.2 Hz, 2H), 3.24 - 2.99 (m, 3H), 2.91 (d, J = 10.9 Hz, 2H), 2.17 (dd, J = 11.3, 2.3 Hz, 2H), 1.55 (s, 1H), 1.03 (s, 6H).

[0650]

[0651] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octane (S38). To a solution of S20a (630 mg, 1.76 mmol) in DCM (10 mL) was added N,N-diisopropylethylamine (1.22 ml, 0.01 mol), the mixture was cooled to 5 °C, and then methanesulfonyl chloride (0.2 ml, 3.0 mmol) was added. After 3 minutes, the reaction was quenched with saturated NaHCO3 solution, the organic layer was separated, dried over Na2SO4, filtered, concentrated, and the residue was dissolved in MeOH (15 mL). The solution was cooled to 10 °C, and then K2CO3 (0.44 g, 0.01 mol) was added. After 15 minutes, the precipitate was filtered off, washed with 10% MeOH in water, and dried in vacuo to give S38 (477 mg, 93.1%) MS (ESI) m / z 292.2 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 8.07 (dd, J = 2.3, 0.8 Hz, 1H), 7.32 (dd, J = 8.8, 2.3 Hz, 1H), 6.26 (d, J = 8.8 Hz, 1H), 4.12 (dd, J = 4.7, 2.4 Hz, 2H), 3.83 (dd, J = 12.3, 2.5 Hz, 2H), 2.92 (dd, J = 12.1, 2.1 Hz, 2H), 2.84 (s, 1H), 2.75 (s, 3H), 1.89 - 1.76 (m, 2H), 1.65 - 1.56 (m, 2H).

[0652]

[0653] Synthesis of tert-butyl 7-(5-iodopyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (S39a). The title compound S39a was prepared according to the method described for the synthesis of compound S1a, but using tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate instead. MS (ESI) m / z 430.2 [M+H] + 。

[0654] Synthesis of 3-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (S39b). The title compound S39b was prepared according to the method described for the synthesis of compound S1, but using S39a instead. MS (ESI) m / z 300.2 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 7.97 (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 9.4, 2.2 Hz, 1H), 7.10 (d, J = 9.3 Hz, 1H), 4.00 (d, J = 12.6 Hz, 2H), 3.30 (d, J = 13.0 Hz, 2H), 3.21 (t, J = 11.5 Hz, 2H), 3.12 (d, J = 13.0 Hz, 2H), 2.21 (s, 2H), 1.87 (d, J = 13.8 Hz, 1H), 1.78 (d, J = 13.7 Hz, 1H), 0.00 (s, 9H).

[0655] Synthesis of 1-(7-(5-ethynylpyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)ethan-1-one (S39). To a mixture of S39b (0.39 g, 1 mmol) and Et3N (0.73 ml, 0.01 mol) in DCM (10 mL) was added acetic anhydride (0.14 ml, 1 mmol). After 5 minutes, the reaction was quenched with 1 M NaOH, the layers were separated and the organic layer was dried over Na2SO4, filtered, concentrated and the residue was dissolved in MeOH (20 mL), then K2CO3 (0.44 g, 3 mmol) was added. After 20 minutes, the reaction was diluted with DCM, washed with water, the organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (60%-100% EtOAc / hexane to 5% MeOH / EtOAc) to give S39 (111 mg, 39%) MS (ESI) m / z 270.2 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.12 (dd, J = 2.3, 0.8 Hz, 1H), 7.48 (dd, J = 9.0, 2.4 Hz, 1H), 6.69 (dd, J = 9.0, 0.8 Hz, 1H), 4.74 - 4.59 (m, 2H), 4.33 - 4.20 (m, 1H), 4.04 (d, J = 13.4 Hz, 1H), 3.42 (dt, J = 13.5, 2.7 Hz, 1H), 3.39 (s, 1H), 3.11 (dddd, J = 11.1, 8.0, 3.2, 2.2 Hz, 2H), 2.87 (dt, J = 13.5, 2.6 Hz, 1H), 2.06 (q, J = 3.0 Hz, 2H), 2.01 - 1.94 (m, 2H), 1.84 (s, 3H).

[0656]

[0657] Synthesis of 3-(5-ethynylpyridin-2-yl)-7-(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane (S40). In a microwave tube, a mixture of S39b (0.21 g, 0.6 mmol), 2-fluoropyridine (0.1 ml, 1 mmol), and sodium bicarbonate (0.24 g, 3 mmol) in NMP (1 mL) was microwave-treated at 130 °C for 20 minutes and then at 150 °C for 20 minutes. The reaction was diluted with DCM, washed with water, the organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain S40 (9 mg, 5%). MS (ESI) m / z 305.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.06 (d, J = 2.3 Hz, 1H), 7.93 (dd, J = 5.1, 2.0 Hz, 1H), 7.25 (dd, J = 9.0, 2.4 Hz, 1H), 7.25 - 7.16 (m, 1H), 6.39 (d, J = 8.7 Hz, 1H), 6.36 - 6.30 (m, 2H), 4.39 - 4.17 (m, 4H), 3.15 - 3.02 (m, 5H), 2.93 (s, 1H), 2.18 - 2.07 (m, 2H), 1.89 (d, J = 3.4 Hz, 2H).

[0658]

[0659] Synthesis of 3-(5-ethynylpyridin-2-yl)-7-(oxetan-3-yl)-3,7-diazabicyclo[3.3.1]nonane (S41). The title compound S41 was prepared according to the method described for the synthesis of compound S1c, but using S39b instead. MS (ESI) m / z 284.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.17 - 7.96 (m, 1H), 7.46 (dd, J = 9.0, 2.4 Hz, 1H), 6.77 - 6.49 (m, 1H), 4.41 (t, J = 6.4 Hz, 2H), 4.26 (t, J = 6.2 Hz, 2H), 4.19 (d, J = 12.9 Hz, 2H), 3.31 (s, 1H), 3.23 - 3.12 (m, 3H), 2.80 - 2.65 (m, 2H), 2.13 - 1.91 (m, 4H), 1.91 - 1.76 (m, 1H), 1.73 - 1.61 (m, 1H).

[0660]

[0661] Synthesis of 3-(5-iodopyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (S43a). The title compound S43a was prepared according to the method proposed for the synthesis of compound S1a, but using 8-oxa-3-azabicyclo[3.2.1]octane instead. MS(ESI) m / z 317.1 [M+H] + 。

[0662] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (S43b). The title compound S43 was prepared according to the method proposed for the synthesis of compound S1, but using S43a instead. MS(ESI) m / z 215.2 [M+H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.17 (dd, J = 2.3, 0.8 Hz, 1H), 7.56 (dd, J = 8.9, 2.3 Hz, 1H), 6.67 (dd, J = 8.9, 0.8 Hz, 1H), 4.46 (dq, J = 4.4, 2.3 Hz, 2H), 3.86 (dt, J = 12.8, 1.1 Hz, 2H), 3.43 (s, 1H), 3.07 (d, J = 2.6 Hz, 1H), 3.03 (d, J = 2.6 Hz, 1H), 2.02 - 1.74 (m, 4H).

[0663]

[0664] Synthesis of 3-(3-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S44a) The title compound S44a was prepared according to the method proposed for the synthesis of compound S3, but using 2-fluoro-5-iodo-3-methylpyridine instead. MS(ESI) m / z 300.3 [M+H] + 。

[0665] Synthesis of 3-(5-ethynyl-3-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S44). The title compound S44 was prepared according to the method proposed for the synthesis of compound S3, but using S44a instead. MS(ESI) m / z 284.2 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 8.24 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.3 Hz, 0H), 7.43 (dd, J = 2.1, 0.9 Hz, 1H), 7.30 (d, J = 1.9 Hz, 0H), 7.19 (d, J = 15.2 Hz, 0H), 5.80 (d, J = 15.1 Hz, 0H), 5.30 (s, 0H), 4.70 (t, J = 6.2 Hz, 3H), 4.59 (s, 2H), 3.76 (s, 1H), 3.35 - 3.26 (m, 2H), 3.18 (d, J = 30.6 Hz, 5H), 3.09 (s, 1H), 2.27 (s, 0H), 2.24 (s, 3H), 1.96 - 1.79 (m, 5H), 0.24 (d, J = 7.3 Hz, 0H), 0.15 (d, J = 6.0 Hz, 0H), 0.08 (s, 0H).

[0666]

[0667] Synthesis of 3-(6-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S45a). The title compound S45a was prepared according to the method proposed for the synthesis of compound S3, but using 6-fluoro-3-iodo-2-methylpyridine instead. MS (ESI) m / z 300.3 [M+H] + 。

[0668] Synthesis of 3-(5-ethynyl-6-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S45). The title compound S45 was prepared according to the method proposed for the synthesis of compound S3, but using S45a instead. MS (ESI) m / z 284.2 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 7.46 (d, J = 8.7 Hz, 1H), 6.28 (d, J = 8.7 Hz, 1H), 5.30 (s, 0H), 4.72 (t, J = 6.3 Hz, 2H), 4.59 (t, J = 5.8 Hz, 2H), 4.07 (d, J = 12.6 Hz, 0H), 3.89 (d, J = 11.0 Hz, 2H), 3.71 (p, J = 6.0 Hz, 1H), 3.26 (d, J = 13.4 Hz, 1H), 3.24 (s, 0H), 3.23 (s, 1H), 3.19 (s, 2H), 3.14 - 3.07 (m, 2H), 2.51 (s, 3H), 1.85 (dd, J = 11.5, 6.7 Hz, 2H), 1.70 (t, J = 6.7 Hz, 1H).

[0669]

[0670] Synthesis of 3-(4-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S46a). The preparation of the title compound S46a was carried out according to the method proposed for the synthesis of compound S3, but 2-fluoro-5-iodo-4-methylpyridine was used instead. MS(ESI) m / z 300.4 [M+H] + 。

[0671] Synthesis of 3-(5-ethynyl-4-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane (S46). The preparation of the title compound S46 was carried out according to the method proposed for the synthesis of compound S3, but S46a was used instead. MS(ESI) m / z 284.2 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.22 (s, 1H), 6.33 (s, 1H), 5.30 (s, 0H), 4.72 (t, J = 6.3 Hz, 2H), 4.59 (t, J = 5.8 Hz, 2H), 3.85 (dd, J = 11.8, 2.4 Hz, 2H), 3.70 (p, J = 6.0 Hz, 1H), 3.24 (s, 0H), 3.23 (s, 1H), 3.22 - 3.09 (m, 4H), 2.34 (d, J = 0.7 Hz, 3H), 1.85 (dd, J = 8.9, 4.3 Hz, 2H), 1.72 - 1.66 (m, 2H).

[0672]

[0673] Synthesis of 4-(5-iodopyridin-2-yl)-1-methylpiperazin-2-one (S47a). The preparation of the title compound S47a was carried out according to the method proposed for the synthesis of compound S1a, but 1-methylpiperazin-2-one hydrochloride was used instead. MS(ESI) m / z 318.0 [M+H] + 。

[0674] Synthesis of 3-(5-ethynyl-4-methylpyridin-2-yl)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane 4-(5-ethynylpyridin-2-yl)-1-methylpiperazin-2-one (S47). The preparation of the title compound S47 was carried out according to the method proposed for the synthesis of compound S3, but S47a was used instead. MS(ESI) m / z 216.1 [M+H] + 。

[0675]

[0676] Synthesis of 1-(5-ethynylpyridin-2-yl)-4-(oxetan-3-yl)piperazine (S48). The title compound S48 was prepared according to the method proposed for the synthesis of compound S1, but 1-(oxetan-3-yl)piperazine was used instead. MS(ESI) m / z 244.16 [M+H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.18 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 8.9, 2.3 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 4.70 (t, J = 6.6 Hz, 3H), 4.63 (t, J = 6.2 Hz, 3H), 3.68 - 3.56 (m, 6H), 3.55 - 3.47 (m, 1H), 3.42 (s, 1H), 2.52 - 2.37 (m, 6H), 1.27 (d, J = 13.9 Hz, 0H).

[0677]

[0678] Synthesis of 5-ethynyl-2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidine (S49). The title compound S49 was prepared according to the method proposed for the synthesis of compound S1, but tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate was used instead. MS(ESI) m / z 245.2 [M+H] + 。

[0679]

[0680] Synthesis of 5-ethynyl-2-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyrimidine (S50). The title compound S50 was prepared according to the method proposed for the synthesis of compound S1, but tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate and 4-oxotetrahydropyran were used instead. MS(ESI) m / z 272.70 [M+H] + 。

[0681]

[0682] Synthesis of tert-butyl 3-((3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)methyl)azetidine-1-carboxylate (S51). The title compound S51 was prepared according to the method proposed for the synthesis of compound S1, but S3b and tert-butyl 3-formylazetidine-1-carboxylate were used instead. MS(ESI) m / z 383.05 [M+H] +。

[0683]

[0684] Synthesis of 3-(5-iodopyrimidin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane (S52a) The preparation of the title compound S52a was carried out according to the method proposed for the synthesis of compound S1c, but using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and 2-chloro-5-iodopyrimidine instead. MS(ESI) m / z 359.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.47 (s, 2H), 4.70 (t, J = 6.2 Hz, 2H), 4.48 (t, J = 5.5 Hz, 2H), 3.87 (p, J = 5.5 Hz, 1H), 3.81 (d, J = 6.1 Hz, 2H), 3.56 (q, J = 13.2 Hz, 4H), 2.74 (q, J = 7.8 Hz, 1H), 1.58 (d, J = 8.9 Hz, 1H).

[0685] Synthesis of 3-(5-ethynylpyrimidin-2-yl)-6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptane (S52) The preparation of the title compound S52 was carried out according to the method proposed for the synthesis of compound S1, but using S52a instead. MS(ESI) m / z 257.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.32 (s, 2H), 4.55 (t, J = 6.1 Hz, 2H), 4.32 (dd, J = 6.0, 4.8 Hz, 2H), 3.72 (ddd, J = 11.1, 6.2, 4.9 Hz, 1H), 3.65 (d, J = 6.0 Hz, 2H), 3.50 (d, J = 13.3 Hz, 2H), 3.43 (d, J = 13.3 Hz, 2H), 3.06 (s, 1H), 2.58 (dt, J = 8.1, 6.1 Hz, 1H), 1.44 (d, J = 8.8 Hz, 1H).

[0686]

[0687] Synthesis of (6-(6-(Oxetan-3-yl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)boronic acid (S53) A suspension of S4a (0.17 g, 0.47 mmol), bis(pinacolato)diboron (0.18 g, 0.72 mmol), potassium acetate (0.17 g, 1.68 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.04 g, 0.05 mmol) in DMF (4.5 mL) was degassed with argon for 5 min and then heated at 90 °C for 1 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed twice with 5% LiCl solution. The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by HPLC and the product was lyophilized to give S53. MS (ESI) m / z 276.2 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.35 (d, J = 1.7 Hz, 1H), 8.31 (dd, J = 9.0, 1.8 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 4.74 - 4.58 (m, 4H), 4.27 - 3.99 (m, 4H), 3.28 - 3.16 (m, 1H), 2.21 - 2.06 (m, 2H).

[0688]

[0689] Synthesis of 3-(5-Ethynylpyridin-2-yl)-8-methyl-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-8-ium iodide (S54 and S55) To a solution of S3 (in acetone, 1 mL) in a vial at 30 °C was added methyl iodide (0.06 mL, 1.0 mmol). The mixture was warmed to 70 °C and stirred. After cooling to room temperature, the reaction was diluted with ether, stirred for 5 min, and the solid was filtered and dried in vacuo to give a 3:1 mixture of isomers (S54:S55), where the major product (S4) has the methyl group in the bridge position. MS (ESI) m / z 284.0 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.08 - 8.02 (m, 1H), 7.50 - 7.40 (m, 1H), 6.58 (d, J = 9.0 Hz, 0H), 6.54 (dd, J = 8.8, 0.9 Hz, 1H), 5.37 (t, J = 8.1 Hz, 1H), 4.86 - 4.70 (m, 5H), 4.05 - 3.94 (m, 3H), 3.88 (d, J = 14.3 Hz, 3H), 3.54 (d, J = 14.7 Hz, 1H), 3.45 (s, 1H), 3.37 (d, J = 2.1 Hz, 1H), 3.34 (s, 4H), 3.30 (s, 1H), 2.37 - 2.27 (m, 2H), 2.21 - 2.11 (m, 1H), 2.07 - 1.94 (m, 2H), 1.94 (s, 1H).

[0690]

[0691] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-((3-methyloxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane (S56). The title compound S56 was prepared according to the method proposed for the synthesis of compound S1, but using 3-(5-iodopyridin-2-yl)-8-((3-methyloxetan-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane instead. MS (ESI) m / z 298.19 [M+H] + 。

[0692]

[0693] Synthesis of 1-(5-ethynylpyridin-2-yl)-4-(tetrahydrofuran-3-yl)piperazine (S57). The title compound S57 was prepared according to the method proposed for the synthesis of compound S50, but using dihydrofuran-3(2H)-one instead. 1 1H-NMR and MS data were the same as those of S14.

[0694]

[0695] Synthesis of 4-(5-ethynylpyrimidin-2-yl)piperazin-2-one (S58a). The title compound S58a was prepared according to the method proposed for the synthesis of compound S47, but using piperazin-2-one and 2-chloro-5-iodopyrimidine instead. MS (ESI) m / z 303.0 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 8.44 (s, 2H), 6.11 (s, 1H), 4.46 (s, 2H), 4.16 - 3.91 (m, 2H), 3.47 (td, J = 5.4, 2.7 Hz, 2H), 3.19 (s, 1H).

[0696] Synthesis of 4-(5-ethynylpyrimidin-2-yl)-1-methylpiperazin-2-one (S58). Sodium hydride (60% oil dispersion, 59 mg, 1.475 mmol) was added to a solution of S58a (115 mg, 0.57 mmol) in THF (5 mL) and DMF (1 mL) at 0 °C. After 15 minutes, methyl iodide (0.15 ml, 2.409 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 h, then quenched with water and partitioned with EtOAc. The separated organic layer was dried over Na2SO4 and concentrated in vacuo to give S58 (124.9 mg, 100%). MS (ESI) m / z 217.1 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.45 (s, 2H), 4.37 (s, 2H), 4.18 - 4.03 (m, 2H), 3.65 (s, 1H), 3.57 - 3.43 (m, 2H), 3.01 (s, 3H).

[0697]

[0698] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane (S59). The title compound S59 was prepared according to the method described for the synthesis of compound S3, but using 2-methoxyacetaldehyde instead. MS (ESI) m / z 303.02 [M+H] + 。

[0699]

[0700] Synthesis of (6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)boronic acid (S60). The title compound S60 was prepared according to the method described for the synthesis of compound S53, but using S3c instead. MS (ESI) m / z 290.2 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.33 (s, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 4.91 (t, J = 7.3 Hz, 3H), 4.76 (dd, J = 7.7, 5.2 Hz, 2H), 4.36 (s, 1H), 4.17 (d, J = 13.4 Hz, 3H), 4.00 (s, 2H), 3.46 (d, J = 13.2 Hz, 2H), 2.28 - 2.10 (m, 2H), 2.01 (d, J = 8.4 Hz, 2H).

[0701]

[0702] Synthesis of 3-(5-ethynylpyridin-2-yl)-8-(pyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S61). A suspension of S20a (0.15 g, 0.42 mmol), sodium bicarbonate (250 mg, 2.9 mmol), and 2-chloropyrimidine (0.17 g, 1.5 mmol) in isopropanol (1.5 mL) was stirred overnight at 65 °C. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and filtered through Celite. The crude mixture was concentrated in vacuo and redissolved in methanol (5 mL). Potassium carbonate (0.29 g, 2.1 mmol) was added and the mixture was stirred for 30 minutes. The reaction was quenched with water and the crude product was extracted into DCM, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (30% → 70% EtOAc → hexanes). MS (ESI) m / z 292.2 [M+H] + 1H NMR (400 MHz, methanol-d4) δ 8.35 (d, J = 4.8 Hz, 2H), 8.17 (dd, J = 2.4, 0.8 Hz, 1H), 7.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.69 (dd, J = 9.0, 0.8 Hz, 1H), 6.64 (t, J = 4.8 Hz, 1H), 4.89 (dq, J = 4.6, 2.3 Hz, 3H), 4.02 (dd, J = 12.4, 2.3 Hz, 3H), 3.42 (s, 1H), 3.13 (dd, J = 12.3, 2.3 Hz, 3H), 2.08 - 1.96 (m, 3H), 1.96 - 1.82 (m, 3H).

[0703]

[0704] 3-(5-Ethynylpyridin-2-yl)-8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane (S62). The title compound S62 was prepared according to the method proposed for the synthesis of compound S63, but 2,2,2-trifluoroethyl trifluoromethanesulfonate was used instead. MS(ESI) m / z 296.20 [M+H] + .

[0705]

[0706] Synthesis of 8-(2,2-difluoroethyl)-3-(5-ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane (S63). To a suspension of reagent 1 (0.2 g, 0.56 mmol) and 2-iodo-1,1-difluoroethane (0.15 g, 0.78 mmol) in 1,4-dioxane (3 ml) was added cesium carbonate 99.95% (0.21 g, 3.35 mmol). The mixture was stirred overnight at 60 °C. Cooled to room temperature and 2,2-difluoroethyl trifluoromethanesulfonate (98% min) (0.17 g, 0.78 mmol) was added. The mixture was warmed to 60 °C for a total of 8 h. Quenched with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (10% EtOAc / Hex). The product was dissolved in methanol (3 ml), potassium carbonate (0.11 g, 0.82 mmol) was added and the mixture was concentrated in the last 1 h, diluted with EtOAc, washed with water, dried over Na2SO4, filtered, concentrated to give S63 (76 mg, 99.7%). MS(ESI) m / z 278.2 [M+H] +

[0707]

[0708] Synthesis of (3-(5-Ethynylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)(3-methyloxetan-3-yl)methanone (S64) To S20a suspended in CH2Cl2 (10 mL) was added 3-methyloxetane-3-carboxylic acid (0.12 g, 1 mmol), Et3N (0.68 ml, 5 mmol), and then HATU (0.48 g, 1 mmol). The mixture was stirred for 1.5 h. The mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in MeOH (20 mL), cooled to 5 °C and potassium carbonate (0.4 g, 3 mmol) was added. After 30 minutes, the reaction was quenched with water and brine, extracted into DCM, dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (60%-100% EtOAc / hexane to 5% MeOH / EtOAc) to give S64.

[0709] MS(ESI) m / z 312.22 [M+H].

[0710] 2.3 Synthesis of A Intermediate

[0711]

[0712] Synthesis of Diethyl 2-(1,1,1-trifluoroprop-2-en-1-yl)malonate (A1a) A mixture of dry THF (5000 mL) and dry CCl4 (600 mL) was cooled to 0 °C and treated with TiCl4 (275 mL, 2.50 mol). The resulting yellow suspension was stirred at 0 °C for 5 minutes and sequentially treated with 1,1,1-trifluoropropan-2-one (140 g, 1.25 mol) and freshly distilled diethyl malonate (200 g, 1.25 mol), then stirred at 0 °C for 0.5 h. The reaction mixture was then treated with a solution of dry pyridine (400 mL) in dry THF (500 mL) and stirred at 0 °C for 1 h, then overnight at room temperature. The reaction mixture was quenched with water and extracted with EtOAc (1 L x 3). The combined organic extracts were washed with brine and saturated NaHCO3, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:PE = 1:50) to give the title compound A1a (298 g, 94%).

[0713] 1 1H NMR (CDCl3, 300 MHz): δ 4.32 - 4.23 (m, 4H), 2.20 (s, 3H), 1.33 - 1.24 (m, 6H).

[0714] Synthesis of Diethyl 2-(1,1,1-trifluoro-2-methylpropan-2-yl)malonate (A1b) A mixture of methylmagnesium iodide (3.0 mol / L in ether, 10 L, 30 mol) and copper(I) chloride (3.5 g, 35 mmol) was stirred at 0 °C and treated over 30 minutes with a solution of compound A1a (178 g, 700 mmol) in dry Et2O (1000 mL). The mixture was then stirred at room temperature for 30 minutes and quenched by dropwise addition of ice-water (1.5 L), followed by aqueous HCl (3 mol / L, 350 mL). The mixture was then extracted with Et2O (1 L x 3). The combined organic extracts were washed with aqueous NaOH (1 N), water, and brine, dried (MgSO4), filtered, and evaporated. The residue, crude compound A1b (90 g, 47%), was used directly in the next step without further purification. MS (ESI) m / z 271 [M+H] + 。 1 H NMR (CDCl3, 300 MHz): δ 4.22 - 4.15 (m, 4H), 3.64 (s, 1H), 1.38 (s, 6H), 1.30 - 1.24 (m, 6H).

[0715] Synthesis of 2-(Ethoxycarbonyl)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A1c) A solution of compound A1b (144 g, 0.53 mol) in a mixture of EtOH (500 mL) and water (500 mL) was treated portionwise with NaOH (19 g, 0.48 mmol) at 0 °C and stirred at room temperature for 5 hours. The reaction mixture was evaporated to a slurry, dissolved in water (1 L), and extracted with Et2O (2 L). The aqueous phase was acidified to pH = 2.0 with 1 M HCl and extracted with EtOAc (1 L x 3). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated to give the title compound A1c (107 g, 84%), which was used directly in the next step without further purification. MS (ESI) m / z 241 [M+H] + 。 1 H NMR (CDCl3, 300 MHz): δ 4.23 (q, J = 5.4 Hz, 2H), 3.69 (s, 1H), 1.40 (s, 6H), 1.27 (t, J = 5.1 Hz, 3H).

[0716] Synthesis of Ethyl 2-((tert-Butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutyrate (A1d) A solution of compound A1c (110 g, 454 mmol) in dry toluene (600 mL) was treated with triethylamine (45.4 g, 454 mmol) and diphenylphosphoryl azide (125 g, 454 mmol). The reaction mixture was refluxed for 1 h, then t-BuOH (46.7 g, 630 mmol) was added. The mixture was refluxed overnight. After cooling to room temperature, the solvent was evaporated and the residue was dissolved in EtOAc (1 L), washed with 5% NaHCO3 solution, dried (MgSO4), filtered and evaporated. The residue was purified by silica gel column chromatography (EtOAc:PE = 1:9) to give crude compound A1d (60 g, 46%), which was used directly in the next step without further purification. MS (ESI) m / z 313 [M+H] + . 1 1H NMR (CDCl3, 300 MHz): δ 5.20 (d, J = 5.7 Hz, 1H), 4.44 (d, J = 10.8 Hz, 1H), 4.25 - 4.16 (m, 2H), 1.44 (s, 9H), 1.39 - 1.26 (m, 6H), 1.19 (m, 3H).

[0717] Synthesis of 2-((tert-Butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutyric acid (A1e) To a solution of compound A1d (380 g, 1214 mmol) in water (2000 mL) and ethanol (2000 mL) was added LiOH·H2O (134 g, 3166 mmol). The mixture was stirred overnight. Diluted with EtOAc, acidified to pH = 2, and extracted with EtOAc (2000 mL x 3). The organic layer was washed with brine, dried over MgSO4, and concentrated to give compound A1e as a white solid (300 g, 86%). 1 1H NMR (CDCl3, 300 MHz): δ 5.20 (d, J = 10.2 Hz, 1H), 4.48 (d, J = 10.2 Hz, 1H), 1.45 (s, 9H), 1.30 (s, 3H), 1.25 (s, 3H).

[0718] Synthesis of (S)-(S)-2-((tert-Butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid 1-phenylethyl ester (A1g) The acid A1e (300 g, 1052 mmol) and (N,N'-dicyclohexylcarbodiimide (325 g, 1578 mmol) were combined in DCM (250 mL) and PhMe (4000 mL). The solution was cooled to 0 °C, then 4-(dimethylamino)pyridine (128 g, 1052 mmol) and (S)-(-)-1-phenylethanol (128 g, 1052 mmol) were added and the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, then the residue was added to EtOAc / water and extracted with EtOAc (2000 mL x 3). The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The crude product was purified by silica gel column chromatography (0 - 8% EtOAc / PE) to give two compounds. The mixture of diastereomers was separated by a chiral column (IA; heptane; IPA (70:30)). The first peak was collected to give compound A1f (105 g, 25%), and the second peak was collected to give compound A1g (80 g, 19%). 1 1H NMR (CDCl3, 300 MHz): δ 7.38 - 7.31 (m, 5H), 5.90 (q, J = 6.3 Hz, 1H), 5.18 (d, J = 9.6 Hz, 1H), 4.48 (d, J = 9.6 Hz, 1H), 1.56 (d, J = 6.9 Hz, 3H), 1.44 (s, 9H), 1.31 (s, 3H), 1.21 (s, 3H). For compound A1g 1 1H NMR (CDCl3, 300 MHz): δ 7.34 - 7.30 (m, 5H), 5.92 (q, J = 6.3 Hz, 1H), 5.20 (d, J = 9.6 Hz, 1H), 4.44 (d, J = 9.6 Hz, 1H), 1.58 (d, J = 6.9 Hz, 3H), 1.45 (s, 9H), 1.21 (s, 3H), 1.11 (s, 3H).

[0719] Synthesis of (S)-2-((tert-Butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A1) Compound A1f (83 g, 214 mmol) was diluted with ethanol (1000 mL). Pd / C (10%, wet, 17 g) was added and the atmosphere was replaced with hydrogen. After stirring for 5 hours, the mixture was filtered through Celite, washed with EtOAc and the filtrate was concentrated to give the product A1 (50 g, 82%). MS (ESI) m / z 186 [M - Boc + 1] + . 11H NMR (300 MHz, DMSO-d6): δ 12.98 (br s, 1H), 7.18 (d, J = 9.6 Hz, 1H), 4.27 (d, J = 9.9 Hz, 1H), 1.36 (s, 9H), 1.14 (s, 6H).

[0720] Synthesis of (R)-2-((tert-Butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A2) Compound A1 g (80 g, 205 mmol) was diluted with ethanol (800 mL). Pd / C (10%, wet, 15 g) was added and the atmosphere was replaced with hydrogen. After stirring for 5 h, the mixture was filtered through Celite, washed with EtOAc and the filtrate was concentrated to give the product A2 (45 g, 77%). MS (ESI) m / z 186 [M - Boc + 1] + . 1 1H NMR (300 MHz, DMSO-d6): δ 7.18 (d, J = 9.6 Hz, 1H), 4.25 (d, J = 9.9 Hz, 1H), 1.36 (s, 9H), 1.14 (s, 6H).

[0721]

[0722] Synthesis of (S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoic acid (A3) To a solution of A1 (10 g, 35.06 mmol) in DCM (160 mL) and MeOH (40 mL) was added HCl (4.0 M in dioxane, 40 mL). The reaction was stirred at room temperature overnight. The reaction was concentrated to dryness (foam). The residue was dissolved in a mixture of dioxane and 2 M NaOH (90 mL), stirred for 5 min, then methyl chloroformate (5.7 mL, 73.33 mmol) was added. After 4 h, the reaction was extracted with 2 x 100 mL DCM (the organic layer was discarded) and the aqueous layer was adjusted to pH ~ 2 with 4 M HCl (~50 mL). The aqueous layer was extracted with 2 x 150 mL EtOAc, the combined EtOAc layers were dried over sodium sulfate, filtered, and concentrated to give A3 (8.54 g, 100%). MS (ESI) m / z 244.0 [M + H] + . 1 1H NMR (400 MHz, methanol-d4) δ 4.57 - 4.41 (m, 1H), 3.66 (d, J = 2.1 Hz, 5H), 1.25 (d, J = 10.0 Hz, 7H).

[0723]

[0724] Synthesis of (S)-4,4,4-trifluoro-3,3-dimethyl-2-(((oxetan-3-yloxy)carbonyl)amino)butanoic acid (A4). The title compound A4 was prepared according to the method proposed for the synthesis of compound A3, but using 4-nitrophenyl oxetane-3-carboxylate instead. MS (ESI) m / z 285.5 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 7.66 (d, J = 9.9 Hz, 1H), 5.37 (tt, J = 6.3, 5.1 Hz, 1H), 4.87 - 4.82 (m, 2H), 4.62 (tdd, J = 7.5, 5.1, 0.9 Hz, 2H), 4.49 - 4.41 (m, 1H), 1.28 (s, 3H), 1.25 (s, 3H).

[0725]

[0726] Synthesis of (S)-2-((cyclopropoxycarbonyl)amino)-3,3-dimethylbutanoic acid (A5) To a solution of cyclopropanol (0.4 ml, 6.37 mmol) in CH3CN (18 mL) at 0 °C was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (DSC) (3.26 g, 12.74 mmol), followed by Et3N (2.66 ml, 19.11 mmol). The reaction mixture was warmed to 40 °C and stirred overnight. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was triturated with DCM, the solid was filtered off, and the filtrate was purified by silica gel column chromatography (10% - 100% EtOAc / hexane). The product (663 mg, 3.33 mmol) was dissolved in THF (5 mL) and L-tert-leucine methyl ester hydrochloride (0.91 g, 5 mmol) and Et3N (1.39 ml, 0.01 mol) were added, the reaction was warmed to 40 °C for 18 h, then at room temperature for 48 h, diluted with EtOAc, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (760 mg, 3.31 mmol) was dissolved in a mixture of methanol (4 mL) / water (2 mL), and lithium hydroxide monohydrate (0.56 g, 0.01 mol) was added. After 16 h, the mixture was concentrated, diluted with EtOAc, washed with brine, the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give A5 1 1H NMR (400 MHz, chloroform-d) δ 4.19 (d, J = 9.6 Hz, 1H), 1.02 (s, 11H), 0.68 (d, J = 4.8 Hz, 5H).

[0727]

[0728] Synthesis of (S)-2-((cyclopropoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A6). The preparation of the title compound A6 was carried out according to the method proposed for the synthesis of compound A3, but using cyclopropyl (2,5-dioxopyrrolidin-1-yl) carbonate instead. 1H NMR (400 MHz, chloroform-d) δ 5.33 (d, J = 9.8 Hz, 1H), 4.53 (d, J = 9.9 Hz, 1H), 4.08–4.01 (m, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 0.81–0.52 (m, 4H).

[0729]

[0730] Synthesis of (S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoic acid (A7). The preparation of the title compound A7 was carried out according to the method proposed for the synthesis of compound A3, but using (S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-3,3-dimethylbutanoic acid (US 2013 / 0183629 A1 (pp. 178-179))

[0731]

[0732] Synthesis of (S)-2-((methoxycarbonyl)amino)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetic acid (A8). The preparation of the title compound A8 was carried out according to the method proposed for the synthesis of compound A3, but using (S)-2-amino-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)acetic acid. MS (ESI) m / z 267.0 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 4.35-4.26 (m, 1H), 3.65 (s, 3H), 1.97 (qd, J = 9.6, 1.7 Hz, 6H).

[0733] 2.4 Synthesis of I Intermediate

[0734]

[0735] Synthesis of tert-butyl ((2S,3S)-4-hydrazino-3-hydroxy-1-(4-iodophenyl)butan-2-yl)carbamate (I1a). To a solution of NH2NH2 (48.3 g, 0.82 mol) in iPrOH (157 mL) at 0 °C was added dropwise ((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate tert-butyl ester (16.1 g, 41.4 mmol) dissolved in DCM (79 mL) over 1 h. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness, diluted with water, filtered, washed with water and dried to give compound I1a (17.0 g, 97%). 1 1H NMR (300 MHz, CDCl3): δ 7.59 (d, J = 7.8 Hz, 2H), 7.02 - 6.96 (m, 2H), 5.03 (d, J = 9.9 Hz, 1H), 3.78 - 3.66 (m, 2H), 2.85 - 2.67 (m, 4H), 2.04 (s, 3H), 1.38 (s, 9H).

[0736] Synthesis of methyl ((S)-1-{(1S,2S)-2-hydroxy-1-(4-iodobenzyl)-3-[N'-((S)-2-methoxycarbonylamino-3,3-dimethylbutanoyl)hydrazino]propylcarbamoyl}-2,2-dimethylpropyl)carbamate (I1). To a solution of I1a (34.0 g, 80.7 mmol) in CH2Cl2 (990 mL) at room temperature was added 4 M hydrochloric acid (198 mL). After stirring at 45 °C for 2 h, LC / MS indicated completion of the reaction and the mixture was concentrated in vacuo. To this crude residue suspended in CH2Cl2 (700 mL) and cooled to -20 °C was added DIPEA (48.2 g, 373.9 mmol), Moc-tBu-Gly (25.53 g, 135.1 mmol), and then HATU (53.4 g, 140.5 mmol). The mixture was slowly warmed to room temperature and stirred for 1 h. The mixture was diluted with DCM (1 L) and washed sequentially with 1 N aqueous HCl solution (400 mL), saturated aqueous NaHCO3 solution (400 mL), water (600 mL x 2), and brine (600 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue which was purified by silica gel column chromatography eluting with EtOAc:petroleum ether = 2:1 to 100% EtOAc to EtOAc:MeOH = 50:1 to give the product I1 (8.2 g, 19.4%). MS (ESI) m / z 664.0 [M+H] + . 11H NMR (300 MHz, CD3OD): δ 7.53 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 4.10 - 4.21 (m, 1H), 3.90 (s, 1H), 3.82 (s, 1H), 3.69 - 3.64 (m, 7H), 2.78 - 2.76 (m, 4H), 0.95 (s, 9H), 0.91 (s, 9H);

[0737]

[0738] Synthesis of tert-butyl 2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)hydrazine-1-carboxylate (I2a) A mixture of tert-butyl ((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (5 g, 12.85 mmol) and tert-butyl hydrazinecarboxylate (3.4 g, 25.69 mmol) in isopropanol (60 mL) was heated to 80 °C for 48 h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0% to 40% EtOAc / DCM) to give 12a (4.86 g, 72.6%). MS (ESI) m / z 522.19 [M+H] +

[0739] Synthesis of methyl ((5S,10S,11S,14S)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazacyclohexadec-14-yl)carbamate (I2) I2a (5.0 g, 10 mmol) was dissolved in DCM (15 mL) and HCl (4.0 M in dioxane, 36 mL). The reaction was stirred overnight and then concentrated under reduced pressure. To the residue was added A3 (4.96 g, 20 mmol) and HATU (8.02 g, 21 mmol) in DCM (100 mL), followed by N,N-diisopropylethylamine (16.7 ml, 96 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (2% to 5% MeOH / DCM) to give I2 (7.39 g, 60%). MS (ESI) m / z 773.0 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 7.52 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 3.71 (q, J = 6.9 Hz, 7H), 3.65 (s, 3H), 1.37 (dd, J = 7.0, 1.7 Hz, 32H), 1.19 - 1.07 (m, 10H).

[0740]

[0741] Synthesis of tert-butyl ((2S,3S)-3-hydroxy-1-(4-iodophenyl)-4-(2-((S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazino)butan-2-yl)carbamate (I3a). The title compound I3a was prepared according to the method proposed for the synthesis of compound I1, but using methyl (S)-(1-hydrazino-3,3-dimethyl-1-oxobutan-2-yl)carbamate instead. MS (ESI) m / z 593.1 [M+H] + 。

[0742] Synthesis of methyl ((5S,10S,11S,14S)-5-(tert-butyl)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-2-oxa-4,7,8,12-tetraazacyclohexadec-14-yl)carbamate The title compound I3 was prepared according to the method proposed for the synthesis of compound I2, but using I3a and A3 instead. MS (ESI) m / z 718.7 [M+H] + 。

[0743]

[0744] Synthesis of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3,3-dimethylbutanoic acid (I4a) L-tert-Leucine (2 g, 15.25 mmol) was dissolved in 10% Na2CO3 solution (80 ml), the solution was cooled to 0 °C, and then 9-fluorenylmethyl chloroformate (4.77 g, 18.44 mmol) in dioxane (31 mL) was added. After 2 h, the reaction mixture was diluted with water, washed with ether and the aqueous layer was adjusted to pH ~ 2 with 6N HCl and extracted with EtOAc. The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated to give I4a. MS (ESI) m / z 353.8 [M+H] + 。

[0745] Synthesis of ((S)-1-(2-((2S,3S)-3-((tert-Butoxycarbonyl)amino)-2-hydroxy-4-(4-iodophenyl)butyl)hydrazino)-3,3-dimethyl-1-oxobutan-2-yl)carbamic acid (9H-fluoren-9-yl)methyl ester (I4)

[0746] To I4a (2.55 g, 7.22 mmol) was added I1a (3 g, 7.12 mmol), HATU (2.7 g, 7.1 mmol) and a mixture of CH2Cl2 / DMF (2:1) (75 ml), followed by N,N-diisopropylethylamine (3 ml, 17.22 mmol). The reaction was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc and washed with saturated NH4Cl and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (2% to 5% MeOH / DCM) to give I4 (2.38 g, 44%) MS (ESI) m / z 757.1 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 8.01 (s, 1H), 7.75 (t, J = 7.5 Hz, 5H), 7.66 - 7.46 (m, 6H), 7.38 (q, J = 7.5 Hz, 4H), 7.34 - 7.27 (m, 1H), 6.95 (dd, J = 16.8, 8.0 Hz, 4H), 5.52 (d, J = 47.2 Hz, 2H), 5.01 (dd, J = 19.2, 10.0 Hz, 1H), 4.48 (dd, J = 10.5, 6.5 Hz, 1H), 4.34 (dt, J = 28.9, 9.8 Hz, 2H), 4.19 (t, J = 6.8 Hz, 2H), 3.91 (dd, J = 45.4, 14.8 Hz, 2H), 3.60 (d, J = 31.0 Hz, 2H), 1.39 (d, J = 16.0 Hz, 13H).

[0747]

[0748] Synthesis of tert-butyl ((2S,3S)-4-(2-((S)-2-((cyclopropoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazino)-3-hydroxy-1-(4-iodophenyl)butan-2-yl)carbamate (I5) The preparation of the title compound I5 was carried out according to the method proposed for the synthesis of compound I2, but using I4 and A5 in place. MS (ESI) m / z 619.4 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 8.02 (s, 0H), 7.59 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 7.9 Hz, 2H), 5.37 (s, 1H), 5.04 (s, 1H), 4.02 (s, 1H), 3.83 (s, 1H), 3.74 - 3.58 (m, 1H), 2.95 (s, 1H), 2.88 (d, J = 0.7 Hz, 1H), 2.85 (d, J = 7.7 Hz, 1H), 2.80 (s, 6H), 1.38 (s, 8H), 1.01 (d, J = 10.5 Hz, 1H), 0.90 (s, 8H), 0.66 (d, J = 4.7 Hz, 4H).

[0749]

[0750] Synthesis of tert-butyl ((2S,3S)-4-(2-((S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)hydrazino)-3-hydroxy-1-(4-iodophenyl)butan-2-yl)carbamate (I6a). The title compound I6a was prepared according to the method proposed for the synthesis of compound I4, but using A7 as an alternative. MS (ESI) m / z 611.5 [M+H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 7.57 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 5.50 (s, 1H), 4.97 (d, J = 9.8 Hz, 1H), 4.37 - 4.17 (m, 1H), 4.03 (td, J = 25.3, 23.8, 9.4 Hz, 2H), 3.68 (s, 4H), 3.50 (s, 0H), 3.17 (qd, J = 7.4, 4.4 Hz, 1H), 2.94 (s, 1H), 2.82 (dt, J = 15.8, 5.5 Hz, 4H), 1.50 (t, J = 7.4 Hz, 1H), 1.46 (dd, J = 17.4, 6.7 Hz, 3H), 1.39 (s, 9H), 0.96 (s, 5H).

[0751] Synthesis of methyl ((5S,8S,9S,14S)-16-fluoro-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)carbamate (I6). The title compound I6 was prepared according to the method proposed for the synthesis of compound I2, but using I6a as an alternative. MS (ESI) m / z 736.1 [M+H] + 。

[0752]

[0753] Synthesis of methyl ((5S,8S,9S,14S)-11-(4-bromo-2,6-difluorobenzyl)-5-(tert-butyl)-9-hydroxy-8-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)carbamate (I7). Methyl (S)-(1-hydrazinyl-3,3-dimethyl-1-oxobutan-2-yl)carbamate (9.2 g, 45 mmol) and 4-bromo-2,6-difluorobenzaldehyde (10 g, 45 mmol) were stirred in THF for 60 minutes at room temperature. 4-Methylbenzenesulfonic acid monohydrate (9.0 g, 48 mmol) was added and the mixture was stirred for an additional 75 minutes. The mixture was cooled to 8 °C and then NaCNBH3 (3.8 g, 61 mmol) was added. The reaction was observed to exotherm to 30 °C. The mixture was stirred at room temperature for 4 hours, then diluted with DCM (200 mL) and quenched with 1 M K3PO4 to pH 12. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was combined with tert-butyl ((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (8.5 g, 22 mmol) in isopropanol (30 mL) and heptane (40 mL). The mixture was stirred at reflux for 40 hours, after which it was cooled to room temperature and diluted with 15 mL of hexane. The product (I7a) was collected by filtration and the solid was rinsed with 20% IPA / hexane. MS (ESI) m / z 797.8 [M+H] + 。

[0754] The title compound I7 was prepared according to the method proposed for the synthesis of compound I1, but substituting methyl (S)-(1-(2-(4-bromo-2,6-difluorobenzyl)hydrazinyl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (I7a) MS (ESI) m / z 869.72 [M+H]. 1 1H NMR (400 MHz, methanol-d4) δ 7.53 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 6.9 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H), 4.16–4.03 (m, 2H), 3.95–3.83 (m, 2H), 3.76–3.57 (m, 11H), 2.90–2.72 (m, 6H), 0.86 (d, J = 23.1 Hz, 18H).

[0755]

[0756] Synthesis of ((5S,8S,9S,14S)-11-(4-bromo-2,6-difluorobenzyl)-5-(tert-butyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)methyl carbamate (I8). Intermediates: I7 and S25. MS(ESI) m / z 1052.92 [M+H]. 1 H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 6.9 Hz, 2H), 6.98 (t, J = 10.5 Hz, 1H), 4.69 (t, J = 6.8 Hz, 2H), 4.21–4.00 (m, 4H), 3.98–3.81 (m, 5H), 3.80–3.62 (m, 9H), 3.25–3.09 (m, 2H), 2.98–2.85 (m, 2H), 2.79 (d, J = 6.6 Hz, 2H), 2.30–2.08 (m, 1H), 2.02–1.72 (m, 6H), 0.87 (d, J = 21.7 Hz, 22H).

[0757]

[0758] ((S)-1-(2-((2S,3S)-3-((S)-2-Amino-4,4,4-trifluoro-3,3-dimethylbutanamido)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)methyl carbamate (I9). A solution of methyl (S)-(4,4,4-trifluoro-1-hydrazino-3,3-dimethyl-1-oxobutan-2-yl)carbamate HCl salt (200 mg, 0.68 mmol) and 4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzaldehyde (P4) (190 mg, 0.75 mmol) in ethanol (5 mL) and acetic acid (0.5 mL) was stirred at 50 °C for 1 hour. The reaction was then cooled to room temperature, diluted with EtOAc, washed with aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was redissolved in MeTHF (10 mL) and cooled to 5 °C. Sodium cyanoborohydride (64 mg, 1.0 mmol) was added, followed by 4-methylbenzenesulfonic acid monohydrate (155 mg, 0.82 mmol). After 1 hour, the reaction was warmed to room temperature and additional sodium cyanoborohydride (64 mg, 1.0 mmol) and 4-methylbenzenesulfonic acid monohydrate (155 mg, 0.82 mmol) were added. After an additional 30 minutes, the reaction was quenched to pH 14 with 2M NaOH. The mixture was then stirred at 40 °C for 30 minutes. The mixture was cooled to room temperature, diluted with EtOAc, and the aqueous layer was removed. The organic layer was dried over Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography (30% → 70% EtOAc in hexanes) to afford methyl (S)-(1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (I9a). 1H NMR (400 MHz, chloroform-d) δ 7.87 (d, J = 2.8 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.22 (t, J = 60.7 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 5.34 (d, J = 9.7 Hz, 1H), 4.30 (d, J = 9.7 Hz, 1H), 4.17 (d, J = 12.9 Hz, 1H), 4.06 (d, J = 13.0 Hz, 1H), 3.67 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H). MS (ESI) m / z 499.2 [M+H].

[0759] Methyl ((S)-(1-(2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (I9a) (0.25 g, 0.50 mmol) was combined with tert-butyl ((S)-2-(4-iodophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate (0.21 g, 0.55 mmol) in heptane (4 mL) and IPA (2 mL). The mixture was stirred overnight in a sealed tube at 90 °C. The crude mixture was cooled to room temperature, concentrated in vacuo, and redissolved in DCM (10 mL) and cooled to 5 °C. 4M hydrochloric acid (4.0 M in dioxane, 0.89 ml) was added and the mixture was stirred overnight, allowing it to warm slowly to room temperature. Concentration in vacuo afforded methyl ((S)-1-(2-((2S,3S)-3-amino-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate (I9b) as the HCl salt. MS (ESI) m / z 787.9 [M+H]. This crude salt (I9b) was combined in DCM (5 mL) with (S)-2-((tert-butoxycarbonyl)amino)-4,4,4-trifluoro-3,3-dimethylbutanoic acid (A1) (0.11 g, 0.38 mmol) and DIPEA (0.27 ml, 2 mmol). HATU (0.14 g, 0.36 mmol) was added. After 20 minutes, the reaction was quenched with aqueous NaOH, the organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting mixture was redissolved in DCM and 4M HCl in dioxane (0.76 ml) was added. After 3.5 h, the mixture was concentrated in vacuo to afford methyl ((S)-1-(2-((2S,3S)-3-((S)-2-amino-4,4,4-trifluoro-3,3-dimethylbutanamido)-2-hydroxy-4-(4-iodophenyl)butyl)-2-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)hydrazino)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate as the HCl salt, which was used without further purification. MS (ESI) m / z 956.2 [M+H].

[0760] 3. Example Compounds, Synthesis, and Characterization

[0761] Example 1

[0762]

[0763] Synthesis of Methyl ((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-10-hydroxy-11-(4-iodobenzyl)-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazacyclohexadecan-14-yl)carbamate (1a). P10 (289.23 mg, 0.88 mmol) and I2 (486 mg, 0.63 mmol) were stirred in a 3:1 mixture of THF / AcOH (7.0 mL) at 55 °C for 1 h. The mixture was cooled to room temperature and polymer-supported sodium cyanoborohydride (2.49 mmol / g, 780.02 mg, 1.94 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then overnight at 28 °C and for 3 h at 35 °C. The mixture was cooled to room temperature, filtered, concentrated under reduced pressure and the residue was purified by column chromatography (45% to 75% EtOAc / hexane) to afford 1a MS (ESI) m / z 1028.3 [M+H] + .

[0764] Synthesis of Methyl ((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-10-hydroxy-15,15-dimethyl-11-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazacyclohexadecan-14-yl)carbamate (1). A solution of 1a (28 mg, 0.027 mmol), S6 (10.4 mg, 0.041 mmol), copper(I) iodide (0.52 mg, 0.002 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (99%, 0.87 mg, 0.004 mmol) in a 3:1 mixture of MeCN:Et3N (1 mL) in a vial was degassed and then heated to 25 °C for a total of 25 min. It was concentrated under reduced pressure. The residue was purified by HPLC and lyophilized to afford 1. MS (ESI) m / z 1131.2 [M+H] + . 11H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 9.9 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.76 (d, J = 9.8 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.32 - 5.96 (m, 1H), 4.96 (s, 1H), 4.61 (dd, J = 8.2, 4.7 Hz, 1H), 4.58 - 4.49 (m, 3H), 4.45 (dd, J = 14.2, 4.8 Hz, 1H), 4.37 (s, 1H), 4.21 (d, J = 9.9 Hz, 1H), 4.04 (d, J = 13.0 Hz, 2H), 3.84 (d, J = 13.2 Hz, 1H), 3.74 (d, J = 11.9 Hz, 1H), 3.67 (d, J = 11.5 Hz, 2H), 3.54 (s, 4H), 3.47 (s, 3H), 2.92 - 2.73 (m, 4H), 2.73 - 2.62 (m, 1H), 2.24 (s, 2H), 1.05 (d, J = 4.5 Hz, 7H), 1.01 (s, 3H), 0.92 (s, 3H).

[0765]

[0766] Example 2

[0767] ((5S,8S,9S,14S)-11-(4-(1-(Difluoromethyl)-1H-imidazol-4-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)methyl carbamate (2) Intermediate: I3, P1 and S7. MS (ESI) m / z 1102.2 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.53 (d, J = 0.8 Hz, 2H), 8.21 (d, J = 9.3 Hz, 1H), 8.17 (d, J = 1.2 Hz, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.59 (t, J = 59.9 Hz, 1H), 7.37 (dd, J = 19.9, 8.1 Hz, 5H), 7.23 (d, J = 7.9 Hz, 3H), 6.83 (d, J = 9.9 Hz, 1H), 4.96 (t, J = 7.6 Hz, 3H), 4.81 (dd, J = 8.2, 5.0 Hz, 3H), 4.44 (d, J = 9.9 Hz, 1H), 4.12 (d, J = 19.4 Hz, 6H), 3.95 (d, J = 13.2 Hz, 1H), 3.75 (d, J = 10.1 Hz, 3H), 3.69 (d, J = 0.8 Hz, 4H), 3.65 (s, 4H), 3.46 (d, J = 14.4 Hz, 3H), 2.90 (d, J = 8.9 Hz, 2H), 2.79 (d, J = 8.9 Hz, 2H), 2.25 - 2.12 (m, 3H), 1.99 (d, J = 8.8 Hz, 2H), 1.14 (s, 4H), 1.10 (s, 4H), 0.86 (s, 12H).

[0768]

[0769] Example 3

[0770] ((5S,10S,11S,14S)-8-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-10-hydroxy-15,15-dimethyl-11-(4-((6-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,8,12-tetraazacyclohexadec-14-yl)methyl carbamate (3). Intermediates: I2, P12 and S3. MS (ESI) m / z 1133.6 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.29 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 9.5 Hz, 1H), 7.69 (dd, J = 8.8, 2.3 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 9.7 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 10.0 Hz, 1H), 6.35 (d, J = 1.9 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.81 - 4.76 (m, 2H), 4.47 (td, J = 13.6, 4.3 Hz, 2H), 4.37 (dd, J = 19.3, 11.6 Hz, 2H), 4.25 (d, J = 9.7 Hz, 1H), 4.15 (s, 2H), 3.99 (d, J = 9.2 Hz, 2H), 3.74 (s, 1H), 3.68 (s, 3H), 3.60 (s, 3H), 3.39 (s, 1H), 3.36 (s, 1H), 2.90 (d, J = 9.0 Hz, 2H), 2.86 - 2.72 (m, 1H), 2.22 (d, J = 8.5 Hz, 2H), 2.07 (d, J = 8.6 Hz, 1H), 1.11 (s, 6H), 1.06 (s, 3H), 0.81 (s, 3H).

[0771]

[0772] Example 4

[0773] ((5S,8S,9S,14S)-5-(tert-Butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(3-methyloxetan-3-carbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazapentadec-14-yl) methyl carbamate (4). Intermediates: 11, P41 and S64. MS (ESI) m / z 1053.33 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.21 (dd, J = 2.2, 0.7 Hz, 1H), 7.90–7.69 (m, 2H), 7.61 (d, J = 2.3 Hz, 1H), 7.33 (t, J = 8.4 Hz, 5H), 7.24 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 9.2 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 5.06 (s, 1H), 4.93 (s, 1H), 4.41 (d, J = 6.0 Hz, 2H), 4.22–4.02 (m, 4H), 3.91 (d, J = 13.2 Hz, 6H), 3.79–3.54 (m, 9H), 3.20 (d, J = 12.0 Hz, 2H), 2.92 (h, J = 5.7, 4.9 Hz, 2H), 2.81 (d, J = 7.9 Hz, 2H), 2.08–1.80 (m, 6H), 1.69 (s, 3H), 0.87 (d, J = 20.1 Hz, 21H).

[0774]

[0775] Example 5

[0776] ((5S,8S,9S,14S)-11-(4-(1-Cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (5) Intermediate: I3, P13 and S3. MS (ESI) m / z 1091.3 [M+H] + 。 1HNMR (400 MHz, methanol-d4) δ 8.20 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.60 (dt, J = 5.5, 2.7 Hz, 2H), 7.24 (t, J = 7.8 Hz, 4H), 7.12 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 9.9 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 4.95 - 4.85 (m, 2H), 4.71 (dd, J = 8.3, 5.0 Hz, 2H), 4.34 (d, J = 10.0 Hz, 1H), 4.26 (d, J = 14.3 Hz, 2H), 4.11 - 3.94 (m, 4H), 3.87 (s, 1H), 3.84 (s, 0H), 3.67 (s, 1H), 3.59 (s, 4H), 3.56 (s, 3H), 3.28 (d, J = 13.9 Hz, 2H), 2.80 (d, J = 9.1 Hz, 2H), 2.69 (d, J = 8.9 Hz, 2H), 2.21 - 2.04 (m, 2H), 1.98 (d, J = 8.6 Hz, 2H), 1.04 (s, 4H), 1.00 (s, 3H), 0.99 - 0.94 (m, 1H), 0.77 (s, 9H).

[0777]

[0778] Example 6

[0779] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (6) Intermediates: I3, P10 and S3. MS (ESI) m / z 1115.3 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.20 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 8.8, 2.3 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 9.9 Hz, 0H), 6.65 (d, J = 2.4 Hz, 1H), 6.12 (tt, J = 55.3, 4.0 Hz, 1H), 4.87 (dd, J = 8.3, 7.0 Hz, 2H), 4.71 (dd, J = 8.3, 5.0 Hz, 2H), 4.54 - 4.42 (m, 2H), 4.38 - 4.31 (m, 1H), 4.26 (d, J = 13.8 Hz, 2H), 4.13 - 3.97 (m, 4H), 3.85 (s, 0H), 3.67 (s, 1H), 3.59 (s, 2H), 3.55 (s, 3H), 3.30 (s, 1H), 3.26 (s, 1H), 2.81 (d, J = 9.3 Hz, 2H), 2.70 (d, J = 9.4 Hz, 2H), 2.17 - 2.06 (m, 2H), 1.98 (d, J = 8.6 Hz, 2H), 1.05 (s, 3H), 1.01 (s, 3H), 0.77 (s, 9H).

[0780]

[0781] Example 7

[0782] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (7). Intermediates: I3, P10 and S7. MS (ESI) m / z 1117.4 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.44 (s, 2H), 8.11 (d, J = 9.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 14.0, 8.2 Hz, 4H), 7.14 (d, J = 8.1 Hz, 2H), 6.73 (d, J = 10.0 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.12 (tt, J = 55.3, 4.0 Hz, 1H), 4.95 - 4.82 (m, 2H), 4.74 - 4.62 (m, 3H), 4.51 (td, J = 14.3, 4.0 Hz, 2H), 4.35 (d, J = 9.9 Hz, 1H), 4.02 (d, J = 19.0 Hz, 4H), 3.86 (d, J = 13.2 Hz, 1H), 3.67 (s, 1H), 3.59 (s, 3H), 3.55 (s, 3H), 3.37 (d, J = 14.5 Hz, 2H), 2.81 (d, J = 8.9 Hz, 2H), 2.70 (d, J = 9.3 Hz, 2H), 2.23 - 2.02 (m, 2H), 1.98 - 1.83 (m, 2H), 1.04 (s, 3H), 1.01 (s, 3H), 0.77 (s, 9H).

[0783]

[0784] Example 8

[0785] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (8). Intermediates: I3, P10 and S6. MS (ESI) m / z 1101.6 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 8.8, 2.2 Hz, 1H), 7.25 (dd, J = 21.0, 8.1 Hz, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 10.3 Hz, 0H), 6.64 (d, J = 2.4 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.12 (tt, J = 55.2, 3.9 Hz, 1H), 4.96 (s, 1H), 4.91 - 4.82 (m, 1H), 4.61 (dd, J = 8.4, 4.6 Hz, 1H), 4.57 - 4.42 (m, 3H), 4.41 (s, 1H), 4.35 (d, J = 6.5 Hz, 1H), 4.02 (d, J = 13.2 Hz, 2H), 3.87 (d, J = 13.2 Hz, 1H), 3.72 - 3.61 (m, 3H), 3.59 (s, 3H), 3.55 (s, 2H), 2.80 (d, J = 8.7 Hz, 1H), 2.70 (d, J = 9.5 Hz, 2H), 2.24 (s, 2H), 1.05 (s, 3H), 1.01 (s, 3H), 0.77 (s, 8H).

[0786]

[0787] Example 9

[0788] ((5S,8S,9S,14S)-11-(2,6-Difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (9). Intermediates: I2, P34 and S6. MS (ESI) m / z 1101.6 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.16 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 7.1 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 10.1 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 4.96 (s, 1H), 4.61 (s, 1H), 4.49 (t, J = 8.9 Hz, 1H), 4.41 (s, 1H), 4.35 (d, J = 9.7 Hz, 1H), 4.18 (d, J = 9.9 Hz, 1H), 4.09 (d, J = 13.1 Hz, 1H), 3.87 (d, J = 13.1 Hz, 1H), 3.77 - 3.55 (m, 8H), 2.82 (d, J = 8.5 Hz, 3H), 2.71 (d, J = 10.1 Hz, 1H), 2.54 (s, 3H), 2.23 (s, 2H), 1.05 (d, J = 7.7 Hz, 9H), 0.92 (s, 3H).

[0789]

[0790] Example 10

[0791] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-8-(4-((6-((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (10). Intermediates: I2, P10 and S8. MS (ESI) m / z 1143.6 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.26 - 8.19 (m, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.61 (dd, J = 8.9, 2.3 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H), 6.72 (d, J = 10.0 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.30 - 5.97 (m, 1H), 4.51 (td, J = 14.2, 3.9 Hz, 3H), 4.35 (d, J = 9.7 Hz, 1H), 4.22 (d, J = 10.0 Hz, 1H), 4.04 (d, J = 12.4 Hz, 4H), 3.60 (s, 3H), 3.57 (s, 3H), 3.48 (d, J = 11.0 Hz, 1H), 2.89 - 2.61 (m, 5H), 1.08 (s, 4H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H).

[0792]

[0793] Example 11

[0794] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (11). Intermediates: I2, P34, and S3. MS (ESI) m / z 1121.3 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.20 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.60 (dd, J = 8.9, 2.3 Hz, 1H), 7.48 (d, J = 7.1 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 10.5 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 9.9 Hz, 1H), 4.93 - 4.82 (m, 2H), 4.74 - 4.63 (m, 2H), 4.34 (d, J = 9.9 Hz, 1H), 4.26 (d, J = 13.5 Hz, 1H), 4.18 (d, J = 10.0 Hz, 1H), 4.09 (d, J = 17.9 Hz, 4H), 3.88 (d, J = 13.1 Hz, 1H), 3.64 (s, 1H), 3.60 (d, J = 2.9 Hz, 6H), 3.28 (d, J = 13.8 Hz, 2H), 2.82 (d, J = 8.6 Hz, 3H), 2.75 - 2.62 (m, 1H), 2.54 (s, 3H), 2.22 - 2.06 (m, 2H), 1.98 (d, J = 8.6 Hz, 2H), 1.06 (s, 6H), 1.04 (s, 3H), 0.93 (s, 3H).

[0795]

[0796] Example 12

[0797] ((5S,8S,9S,14S)-11-(4-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(6-(Oxetan-3-yl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)methyl carbamate (12). Intermediates: I3, P4, and S4. MS (ESI) m / z 1087.8 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.33 (s, 1H), 8.15 (d, J = 9.4 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.52 (t, J = 59.9 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 7.8 Hz, 3H), 7.22 (d, J = 7.9 Hz, 3H), 6.93 (d, J = 2.7 Hz, 1H), 6.78 (d, J = 9.2 Hz, 2H), 4.70 - 4.57 (m, 2H), 4.44 (d, J = 9.7 Hz, 1H), 4.13 (d, J = 12.4 Hz, 3H), 3.97 (d, J = 13.0 Hz, 1H), 3.76 (s, 1H), 3.69 (s, 4H), 3.65 (s, 3H), 2.90 (d, J = 8.7 Hz, 2H), 2.80 (d, J = 11.1 Hz, 2H), 2.11 (d, J = 10.6 Hz, 1H), 1.39 - 1.23 (m, 2H), 1.15 (s, 4H), 1.11 (s, 4H), 0.86 (s, 11H).

[0798]

[0799] Example 13

[0800] Methyl ((5S,8S,9S,14S)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-8-(4-((6-((R)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)ethynyl)benzyl)-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)carbamate (13). Intermediates: I3, P4 and S8. MS (ESI) m / z 1073.9 [M+H] + 。 1HNMR (400 MHz, methanol-d4) δ 8.30 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.75 - 7.59 (m, 2H), 7.56 (dd, J = 7.4, 3.4 Hz, 1H), 7.53 (t, J = 59.8 Hz, 2H), 7.45 (d, J = 8.2 Hz, 3H), 7.32 (d, J = 7.9 Hz, 3H), 7.22 (d, J = 8.1 Hz, 3H), 7.03 - 6.88 (m, 3H), 6.82 (d, J = 10.0 Hz, 1H), 4.62 (dd, J = 22.7, 13.0 Hz, 2H), 4.44 (d, J = 9.7 Hz, 1H), 4.12 (d, J = 12.2 Hz, 6H), 3.97 (d, J = 13.1 Hz, 2H), 3.85 (t, J = 12.6 Hz, 1H), 3.76 (s, 2H), 3.69 (s, 4H), 3.59 (d, J = 10.8 Hz, 2H), 3.01 - 2.70 (m, 6H), 1.14 (s, 4H), 1.11 (s, 4H), 0.86 (s, 12H).

[0801]

[0802] Example 14

[0803] Methyl ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)carbamate (14). Intermediates: I2, P17, and S3. MS (ESI) m / z 1176.1 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.20 (d, J = 2.3 Hz, 1H), 8.11 (d, J = 9.3 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.25 (dd, J = 13.9, 8.3 Hz, 4H), 7.12 (d, J = 8.0 Hz, 2H), 6.75 (dd, J = 17.1, 9.4 Hz, 2H), 6.59 (d, J = 2.4 Hz, 1H), 4.97 (dq, J = 8.2, 3.8 Hz, 1H), 4.87 (t, J = 7.6 Hz, 3H), 4.71 (dd, J = 8.3, 5.0 Hz, 3H), 4.52 - 4.32 (m, 1H), 4.32 - 4.18 (m, 3H), 4.17 - 3.99 (m, 6H), 3.97 (d, J = 4.7 Hz, 2H), 3.84 (td, J = 8.3, 5.4 Hz, 2H), 3.58 (d, J = 9.5 Hz, 8H), 3.27 (d, J = 13.9 Hz, 3H), 2.80 - 2.52 (m, 4H), 2.45 - 2.33 (m, 1H), 2.33 - 2.23 (m, 1H), 2.13 (d, J = 10.7 Hz, 2H), 2.03 - 1.92 (m, 2H), 1.07 (s, 4H), 1.05 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H).

[0804]

[0805] Example 15

[0806] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (15). Intermediates: I2, P18 and S3. MS (ESI) m / z 1176.1 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 8.11 (d, J = 9.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.25 (dd, J = 14.4, 8.2 Hz, 4H), 7.12 (d, J = 8.0 Hz, 2H), 6.74 (t, J = 10.2 Hz, 2H), 6.59 (d, J = 2.4 Hz, 1H), 4.98 (dd, J = 8.3, 3.9 Hz, 1H), 4.69 (t, J = 6.7 Hz, 2H), 4.35 (d, J = 9.9 Hz, 1H), 4.22 (d, J = 10.0 Hz, 1H), 4.03 (dd, J = 14.5, 7.1 Hz, 3H), 3.97 (d, J = 4.7 Hz, 2H), 3.90 - 3.79 (m, 2H), 3.63 (s, 1H), 3.58 (d, J = 9.2 Hz, 6H), 2.81 (d, J = 7.8 Hz, 2H), 2.68 (d, J = 10.0 Hz, 1H), 2.49 - 2.33 (m, 1H), 2.33 - 2.21 (m, 1H), 2.10 (s, 1H), 1.94 (s, 0H), 1.07 (s, 3H), 1.05 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H).

[0807]

[0808] Example 16

[0809] ((5S,8S,9S,14S)-11-(2,6-difluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)methyl carbamate (16). Intermediates: I2, P19 and S3. MS (ESI) m / z 1177.2 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.61 (s, 1H), 7.59 (d, J = 2.3 Hz, 2H), 7.25 (dd, J = 12.2, 8.1 Hz, 4H), 7.12 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 10.2 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 4.87 (t, J = 7.6 Hz, 3H), 4.71 (dd, J = 8.3, 5.0 Hz, 2H), 4.35 (d, J = 9.9 Hz, 1H), 4.30 - 4.13 (m, 2H), 4.03 (d, J = 12.6 Hz, 3H), 3.84 (d, J = 13.3 Hz, 1H), 3.58 (d, J = 8.2 Hz, 5H), 3.28 (d, J = 13.9 Hz, 2H), 2.81 (d, J = 7.8 Hz, 2H), 2.72 (d, J = 15.2 Hz, 1H), 2.12 (s, 1H), 1.98 (d, J = 8.6 Hz, 2H), 1.10 (s, 6H), 1.07 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H).

[0810]

[0811] Example 17

[0812] ((5S,8S,9S,14S)-11-(4-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-8-(4-((6-(8-(Dimethylcarbamoyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)methyl carbamate (17). Intermediates: I2, P7 and S24. MS (ESI) m / z 1177.2 [M+H] +。1H NMR (400 MHz, methanol-d4) δ 8.53 (d, J = 0.7 Hz, 1H), 8.22 - 8.13 (m, 2H), 8.11 (s, 1H), 7.86 (dd, J = 9.3, 2.2 Hz, 1H), 7.50 (s, 1H), 7.40 - 7.30 (m, 2H), 7.23 (dd, J = 8.2, 5.7 Hz, 4H), 7.17 (d, J = 9.9 Hz, 1H), 7.10 (d, J = 9.3 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 4.50 - 4.37 (m, 1H), 4.35 - 4.23 (m, 3H), 4.12 (t, J = 11.1 Hz, 2H), 4.00 - 3.87 (m, 3H), 3.66 (d, J = 10.3 Hz, 7H), 3.43 - 3.33 (m, 2H), 2.96 (s, 6H), 2.94 - 2.69 (m, 2H), 1.96 (t, J = 5.3 Hz, 2H), 1.78 (t, J = 6.9 Hz, 2H), 1.26 - 1.07 (m, 9H), 1.02 (s, 3H).

[0813]

[0814] Example 18

[0815] ((5S,8S,9S,14S)-11-(4-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-8-(4-((6-(8-((S)-tetrahydrofuran-2-carbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (18). Intermediates: I2, P7 and S25. MS (ESI) m / z 1177.2 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.44 (s, 1H), 8.13 - 8.05 (m, 2H), 8.03 (s, 1H), 7.68 (t, J = 8.5 Hz, 1H), 7.41 (s, 1H), 7.31 - 7.22 (m, 2H), 7.20 - 7.05 (m, 5H), 6.96 - 6.84 (m, 1H), 6.72 (d, J = 10.0 Hz, 1H), 4.75 - 4.65 (m, 5H), 4.60 (dd, J = 7.6, 6.2 Hz, 2H), 4.40 - 4.26 (m, 1H), 4.25 - 4.12 (m, 1H), 4.10 - 3.87 (m, 4H), 3.87 - 3.71 (m, 3H), 3.58 (d, J = 10.7 Hz, 6H), 3.17 - 2.96 (m, 2H), 2.89 - 2.59 (m, 4H), 2.19 - 1.93 (m, 2H), 1.93 - 1.67 (m, 4H), 1.15 - 0.96 (m, 9H), 0.94 (s, 3H).

[0816]

[0817] Example 19

[0818] ((5S,8S,9S,14S)-11-(4-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(3-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (19). Intermediates: I2, P7 and S26. MS (ESI) m / z 1177.2 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.54 (d, J = 0.7 Hz, 1H), 8.26 - 8.22 (m, 1H), 8.17 (d, J = 9.4 Hz, 1H), 8.12 (s, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.51 (s, 1H), 7.39 - 7.32 (m, 2H), 7.24 (t, J = 8.3 Hz, 4H), 7.17 (d, J = 9.8 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 4.80 (ddtd, J = 4.5, 2.0, 1.0, 0.5 Hz, 1H), 4.76 - 4.69 (m, 4H), 4.50 - 4.37 (m, 1H), 4.36 - 4.25 (m, 1H), 4.13 (t, J = 10.7 Hz, 3H), 3.93 (d, J = 13.2 Hz, 1H), 3.68 (d, J = 10.5 Hz, 6H), 2.97 - 2.66 (m, 6H), 2.33 - 2.10 (m, 3H), 1.26 - 1.08 (m, 9H), 1.03 (s, 3H).

[0819]

[0820] Example 20

[0821] ((5S,8S,9S,14S)-8-(4-((6-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadecan-14-yl) methyl carbamate (20). Intermediates: I2, P7 and S27. MS (ESI) m / z 1086.3 [M+H] + 。 1HNMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J = 1.9 Hz, 1H), 7.93 (dd, J = 9.4, 2.0 Hz, 1H), 7.69 - 7.60 (m, 1H), 7.56 (dd, J = 7.2, 3.3 Hz, 0H), 7.51 (s, 0H), 7.40 - 7.33 (m, 2H), 7.25 (d, J = 8.0 Hz, 4H), 7.17 (d, J = 9.9 Hz, 1H), 6.83 (d, J = 9.3 Hz, 1H), 4.86 (s, 4H), 4.49 (s, 4H), 4.43 (d, J = 3.7 Hz, 1H), 4.36 - 4.25 (m, 1H), 4.24 - 4.05 (m, 2H), 3.92 (d, J = 13.1 Hz, 1H), 3.67 (d, J = 7.6 Hz, 7H), 2.99 - 2.70 (m, 4H), 1.23 - 1.06 (m, 9H), 1.03 (s, 3H).

[0822]

[0823] Example 21

[0824] ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (21). Intermediates: I2, P10 and S2. MS (ESI) m / z 1143.2 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.18 (d, J = 2.3 Hz, 1H), 8.06 (d, J = 9.3 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.58 (dd, J = 8.9, 2.3 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 9.7 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.71 - 6.61 (m, 2H), 6.12 (tt, J = 55.4, 4.0 Hz, 1H), 4.50 (td, J = 14.3, 3.9 Hz, 2H), 4.34 (d, J = 9.6 Hz, 1H), 4.29 - 4.18 (m, 1H), 4.04 (d, J = 13.0 Hz, 6H), 3.84 (d, J = 13.2 Hz, 1H), 3.63 (s, 3H), 3.56 (s, 3H), 3.50 (s, 2H), 3.10 (s, 3H), 2.81 (d, J = 8.1 Hz, 2H), 2.69 (d, J = 9.4 Hz, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H).

[0825]

[0826] Example 22

[0827] ((5S,8S,9S,14S)-5-(tert-Butyl)-11-(2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)-9-hydroxy-15,15-dimethyl-8-(4-((6-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (22). Intermediate 11, P41 and S3. MS (ESI) m / z 1011.29 [M+H] + 。 11H NMR (400 MHz, methanol-d4)) δ 8.30 (d, J = 2.2 Hz, 1H), 7.70 (dd, J = 8.8, 2.3 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.33 (d, J = 7.7 Hz, 5H), 7.23 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 4.96 (t, J = 7.6 Hz, 2H), 4.82–4.77 (m, 2H), 4.35 (d, J = 13.8 Hz, 2H), 4.13 (d, J = 13.4 Hz, 4H), 3.93 (s, 6H), 3.67 (d, J = 6.4 Hz, 8H), 3.38 (d, J = 13.9 Hz, 2H), 3.00–2.77 (m, 5H), 2.31–2.20 (m, 2H), 2.14–2.04 (m, 2H), 0.87 (d, J = 20.7 Hz, 21H).

[0828]

[0829] Example 23

[0830] ((5S,8S,9S,14S)-11-(4-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-9-hydroxy-15,15-dimethyl-8-(4-((2-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (23). Intermediates: I3, P4 and S7. MS (ESI) m / z 1102.5 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.53 (s, 2H), 8.20 (d, J = 9.4 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.53 (t, J = 59.9, 59.4 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 2.8 Hz, 1H), 6.83 (d, J = 9.9 Hz, 1H), 5.03 - 4.92 (m, 2H), 4.83 - 4.76 (m, 2H), 4.44 (d, J = 10.0 Hz, 1H), 4.16 - 4.05 (m, 2H), 3.97 (d, J = 13.2 Hz, 1H), 3.85 - 3.71 (m, 1H), 3.69 (s, 3H), 3.65 (s, 3H), 3.54 - 3.39 (m, 2H), 2.96 - 2.72 (m, 3H), 2.27 - 2.13 (m, 2H), 2.04 - 1.91 (m, 2H), 1.14 (s, 3H), 1.11 (s, 3H), 0.86 (s, 9H).

[0831]

[0832] Example 24

[0833] ((5S,8S,9S,14S)-11-(2,6-Difluoro-4-(pyrimidin-2-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadecan-14-yl) methyl carbamate (24). Intermediates: I2, P16 and S29. MS (ESI) m / z 1104.3 [M + H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.87 (d, J = 4.9 Hz, 2H), 8.52 (s, 2H), 8.19 (d, J = 9.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.41 (t, J = 4.9 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 10.1 Hz, 1H), 6.82 (d, J = 10.1 Hz, 1H), 5.18 (s, 1H), 4.99 - 4.90 (m, 2H), 4.64 - 4.55 (m, 1H), 4.44 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.24 - 4.10 (m, 2H), 3.98 (d, J = 13.0 Hz, 1H), 3.90 (d, J = 12.5 Hz, 1H), 3.85 - 3.72 (m, 3H), 3.69 (s, 3H), 3.67 (s, 3H), 2.96 - 2.74 (m, 4H), 2.33 (s, 2H), 1.15 (s, 6H), 1.11 (s, 3H), 1.02 (s, 3H).

[0834]

[0835] Example 25

[0836] Methyl ((5S,8S,9S,14S)-11-(4-(1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)carbamate (25). Intermediates: I2, P10 and S29. MS (ESI) m / z 1156.4 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.52 (s, 2H), 8.18 (d, J = 9.3 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.22 (tt, J = 55.5, 4.0 Hz, 1H), 5.18 (s, 1H), 5.01 - 4.90 (m, 2H), 4.72 (s, 1H), 4.60 (td, J = 14.1, 3.7 Hz, 4H), 4.52 (s, 0H), 4.44 (d, J = 9.9 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.20 - 4.07 (m, 2H), 3.98 - 3.86 (m, 2H), 3.81 (d, J = 12.8 Hz, 1H), 3.76 - 3.71 (m, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.00 - 2.71 (m, 4H), 2.34 (s, 2H), 1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.03 (s, 3H).

[0837]

[0838] Example 26

[0839] ((5S,8S,9S,14S)-8-(4-((6-(3-Oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)pyridin-3-yl)ethynyl)benzyl)-11-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadecan-14-yl) methyl carbamate (26). Intermediates: I2, P4, and S28. MS (ESI) m / z 1115.4 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.17 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 9.4 Hz, 1H), 8.01 (d, J = 2.8 Hz, 1H), 7.56 (dd, J = 8.8, 2.4 Hz, 1H), 7.44 (t, J = 59.9 Hz, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 2.7 Hz, 1H), 6.78 (d, J = 9.1 Hz, 1H), 6.69 (d, J = 10.0 Hz, 1H), 4.70 - 4.61 (m, 2H), 4.34 (d, J = 9.8 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1H), 4.08 - 4.00 (m, 4H), 3.94 (d, J = 13.0 Hz, 2H), 3.85 (d, J = 13.1 Hz, 1H), 3.64 (s, 1H), 3.60 (s, 3H), 3.58 - 3.54 (m, 4H), 3.42 (d, J = 14.4 Hz, 3H), 2.85 - 2.62 (m, 4H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H).

[0840]

[0841] Example 27

[0842] ((5S,8S,9S,14S)-11-(4-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (27). Intermediates: I2, P3 and S6. MS (ESI) m / z 1149.3 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 9.4 Hz, 1H), 7.60 (dd, J = 8.8, 2.3 Hz, 1H), 7.42 (d, J = 7.5 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 10.1 Hz, 1H), 6.71 (d, J = 10.0 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 4.96 (s, 1H), 4.92 - 4.78 (m, 2H), 4.61 (s, 1H), 4.55 - 4.44 (m, 1H), 4.41 (s, 1H), 4.34 (d, J = 9.8 Hz, 1H), 4.19 (d, J = 10.0 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.87 (d, J = 13.1 Hz, 1H), 3.72 - 3.61 (m, 2H), 3.60 (s, 3H), 3.58 (s, 3H), 2.89 - 2.75 (m, 3H), 2.73 - 2.61 (m, 1H), 2.43 (ddd, J = 13.1, 8.5, 4.9 Hz, 1H), 2.23 (s, 2H), 1.27 - 1.18 (m, 2H), 1.10 - 1.01 (m, 11H), 0.93 (s, 3H).

[0843]

[0844] Example 28

[0845] ((5S,8S,9S,14S)-11-(4-(1-Cyclopropyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)methyl carbamate (28). Intermediates: I2, P21 and S6. MS (ESI) m / z 1095.8 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.16 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 9.5 Hz, 1H), 7.62 - 7.57 (m, 3H), 7.56 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.04 (s, 1H), 6.67 (d, J = 9.7 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 4.96 (s, 1H), 4.89 - 4.83 (m, 1H), 4.84 - 4.78 (m, 1H), 4.65 - 4.54 (m, 1H), 4.54 - 4.44 (m, 2H), 4.41 (s, 1H), 4.30 (d, J = 9.9 Hz, 1H), 4.16 (d, J = 9.7 Hz, 1H), 4.12 - 4.00 (m, 1H), 3.88 (d, J = 13.2 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 3.73 - 3.60 (m, 2H), 3.60 - 3.53 (m, 4H), 3.51 (s, 3H), 2.87 - 2.76 (m, 2H), 2.76 - 2.59 (m, 2H), 2.23 (s, 2H), 1.07 - 0.94 (m, 10H), 0.92 (s, 3H), 0.72 (s, 3H).

[0846]

[0847] Example 29

[0848] ((5S,8S,9S,14S)-11-(4-(1-(Difluoromethyl)-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((6-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-3-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)methyl carbamate (29). Intermediates: I2, P6 and S6. MS (ESI) m / z 1105.9 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.25 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 9.3 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.69 (dd, J = 8.8, 2.3 Hz, 1H), 7.49 (t, J = 59.7 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 9.4 Hz, 1H), 6.86 (d, J = 2.7 Hz, 1H), 6.77 (d, J = 9.9 Hz, 1H), 6.66 (d, J = 8.7 Hz, 1H), 5.05 (s, 1H), 4.95 (dd, J = 8.4, 6.5 Hz, 1H), 4.93 - 4.87 (m, 1H), 4.70 (dd, J = 8.5, 4.6 Hz, 1H), 4.66 - 4.53 (m, 2H), 4.50 (s, 1H), 4.40 (d, J = 9.9 Hz, 1H), 4.24 (d, J = 9.8 Hz, 1H), 4.21 - 4.12 (m, 1H), 4.01 (d, J = 13.2 Hz, 1H), 3.88 (d, J = 13.2 Hz, 1H), 3.82 - 3.69 (m, 2H), 3.68 (s, 3H), 3.59 (s, 3H), 2.96 - 2.66 (m, 4H), 2.33 (s, 2H), 1.12 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 0.83 (s, 3H).

[0849]

[0850] Example 30

[0851] ((5S,8S,9S,14S)-11-(4-(1-Cyclopropyl-1H-pyrazol-3-yl)benzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)methyl carbamate (30). Intermediates: I2, P21 and S29. MS (ESI) m / z 1096.7 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.51 (s, 2H), 8.10 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 6.76 (d, J = 10.1 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 5.18 (s, 1H), 4.93 (dt, J = 20.6, 7.3 Hz, 1H), 4.72 (s, 1H), 4.65 - 4.55 (m, 1H), 4.51 (s, 0H), 4.40 (d, J = 7.8 Hz, 1H), 4.25 (d, J = 7.8 Hz, 1H), 4.15 (s, 1H), 4.02 - 3.78 (m, 3H), 3.67 (s, 3H), 3.66 (d, J = 3.8 Hz, 1H), 3.59 (s, 3H), 2.94 - 2.67 (m, 4H), 2.41 - 2.30 (m, 2H), 2.05 - 1.99 (m, 1H), 1.93 (s, 1H), 1.15 - 1.04 (m, 10H), 1.01 (s, 3H), 0.81 (s, 3H).

[0852]

[0853] Example 31

[0854] ((5S,8S,9S,14S)-11-(4-(1-Cyclopropyl-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl) methyl carbamate (31). Intermediates: I2, P13 and S29. MS (ESI) m / z 1132.3 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.51 (s, 2H), 8.15 (d, J = 9.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.38 - 7.27 (m, 4H), 7.23 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 10.0 Hz, 1H), 6.77 (d, J = 9.8 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.18 (s, 1H), 4.93 (dt, J = 20.5, 7.3 Hz, 2H), 4.72 (s, 1H), 4.60 (td, J = 12.1, 11.2, 5.5 Hz, 1H), 4.51 (s, 1H), 4.46 - 4.39 (m, 1H), 4.36 - 4.24 (m, 1H), 4.18 - 4.07 (m, 2H), 3.93 (d, J = 11.4 Hz, 1H), 3.89 (s, 1H), 3.80 (d, J = 12.7 Hz, 1H), 3.76 - 3.67 (m, 5H), 3.66 (s, 2H), 2.96 - 2.70 (m, 4H), 2.33 (s, 2H), 1.22 - 1.04 (m, 12H), 1.02 (s, 3H).

[0855]

[0856] Example 32

[0857] ((5S,8S,9S,14S)-11-(4-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzyl)-16,16,16-trifluoro-9-hydroxy-15,15-dimethyl-8-(4-((2-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)pyrimidin-5-yl)ethynyl)benzyl)-3,6,13-trioxo-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-2-oxa-4,7,11,12-tetraazacyclohexadec-14-yl)methyl carbamate (32). Intermediates: I2, P4 and S29. MS (ESI) m / z 1142.4 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.51 (s, 2H), 8.14 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.52 (t, J = 59.9 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.34 (d...

Claims

1. A compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5- to 6-membered heterocycle having 1 to 3 heteroatoms selected from N, O and S, wherein the 5- to 6-membered heterocycle is optionally substituted with 1 to 3 R a groups; R 2 and R 3 each independently is C 1-4 alkyl, C 3-6 cycloalkyl, or O-R 2A where each R 2A is independently C 1-4 alkyl, C 3-6 cycloalkyl or a 4-membered heterocyclic group having 1 O heteroatom, R 4 is C 1-4 alkyl or C 1-4 haloalkyl; R 7 is C 1-4 alkyl or C 1-4 haloalkyl; R 5 ,R 6 ,R 8 and R 9 each independently is C 1-2 alkyl or C 1-2 haloalkyl; R 10a and R 10b each is a halogen; Each R a is independently C 1-4 alkyl, C 1-4 alkyl substituted with 1 to 2 groups selected from hydroxy and C 1-4 alkoxy, or C 1-4 haloalkyl; X 1 is a 6-aryl or 5- to 6-membered heteroaryl having 1 to 3 N heteroatoms, wherein the 6-aryl or 5- to 6-membered heteroaryl is each optionally substituted with 1 to 4 -CH3 groups; X 2 is a 4- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, wherein the 4- to 10-membered heterocyclic group is optionally substituted with one R 11 substituent and is optionally substituted with one R b group; R 11 is a 4- to 6-membered heterocyclic group having 1 O heteroatom; and Each R b is independently halogen or oxo.

2. The compound according to claim 1, wherein R 1 is a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, and the 5- to 6-membered heteroaryl is optionally substituted with 1 to 3 R a groups.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently:

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each methoxy.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-4 haloalkyl.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is CF3.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1-4 haloalkyl.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 7 is CF3.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 5 and R6 is C 1-2 alkyl group.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are methyl.

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are C 1-2 alkyl group.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are methyl.

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 10a and R 10b are each fluorine.

14. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is independently:

15. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is:

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R a is:

17. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R a is C 1-4 haloalkyl.

18. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R a is:

19. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 1 is pyrimidine or pyridine.

20. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 1 is:

21. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 2 is wherein: a) R P1 ,R P2 ,R P3 and R P4 are each hydrogen; b) R P1 and R P3 together form a –CH2– or –CH2CH2– group, and R P2 and R P4 are each hydrogen; c) R P2 and R P4 together to form a –CH2– or –CH2CH2– group, and R P1 and R P3 are each hydrogen; d) R P1 and R P4 together to form a –CH2– group, and R P2 and R P3 are each hydrogen; or e) R P2 and R P3 together form a –CH2– group, and R P1 and R P4 are each hydrogen.

22. The compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein: R P1 and R P3 together to form a –CH2– or –CH2CH2– group, and R P2 and R P4 are each hydrogen; or R P2 and R P4 together to form a –CH2- or –CH2CH2- group, and R P1 and R P3 are each hydrogen.

23. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein X 2 is:

24. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein X 2 is:

25. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 11 is oxetan-3-yl, tetrahydrofuran-3-yl or tetrahydropyran-4-yl.

26. The compound according to claim 1 or 2, wherein the compound of formula (Ia) is a compound of formula (Ic): or a pharmaceutically acceptable salt thereof, wherein: Z 1 and Z 2 are each independently N or CH.

27. The compound according to claim 1 or 2, wherein the compound of formula (Ia) is a compound of formula (Id): or a pharmaceutically acceptable salt thereof, wherein: X 2 is a 4- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O and S, wherein the 4- to 10-membered heterocyclic group is optionally substituted with 1 R b group.

28. The compound according to claim 1 or 2, wherein the compound of formula (Ia) is a compound of formula (Ie): or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5- to 6-membered heterocycle having 1 to 3 heteroatoms selected from N, O, and S; X 2 is a 4- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclic group is optionally substituted with 1 R b group.

29. A compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: R 1 For R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10a 、R 10b 、X 1 and X 2 as defined in claim 1 or 2.

30. A compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X 2 For R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10a 、R 10b and X 1 as defined in claim 1 or 2.

31. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

32. The pharmaceutical composition according to claim 31, which further comprises one, two, three or four additional therapeutic agents.

33. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is selected from: HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds targeting the HIV capsid, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 virion infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic cell ICAM-3-grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, and pharmacokinetic enhancers, in any combination thereof.

34. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is an HIV non-catalytic site integrase inhibitor.

35. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is selected from: HIV protease inhibitory compounds, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and pharmacokinetic enhancers, or any combination thereof.

36. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is selected from: abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate.

37. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is selected from: tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate.

38. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is selected from: or a pharmaceutically acceptable salt thereof.

39. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is selected from: or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is selected from: or a pharmaceutically acceptable salt thereof.

41. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is selected from: or a pharmaceutically acceptable salt thereof.

42. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is selected from: abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, emtricitabine, lamivudine, GS-9131, dolutegravir, and cabotegravir.

43. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is selected from: bictegravir, emtricitabine, and GS-9131.

44. Use of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of human immunodeficiency virus (HIV) infection.

45. The use according to claim 44, wherein the drug is administered in combination with one, two, three or four additional therapeutic agents.

46. The use according to claim 45, wherein the additional therapeutic agents are selected from: HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds targeting the HIV capsid, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors and pharmacokinetic enhancers, or any combination thereof.

47. The use according to claim 45, wherein the additional therapeutic agent is an HIV non-catalytic site integrase inhibitor.

48. The use according to claim 45, wherein the additional therapeutic agents are selected from: HIV protease inhibitory compounds, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors and pharmacokinetic enhancers, or any combination thereof.

49. The use according to claim 45, wherein the additional therapeutic agents are selected from: abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate.

50. The use according to claim 45, wherein the additional therapeutic agent is selected from: tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate.

51. The use according to claim 45, wherein the additional therapeutic agent is administered simultaneously with the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

52. The use according to claim 45, wherein the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof is combined with the additional therapeutic agent in a single dosage form for simultaneous administration.

53. The use according to claim 45, wherein the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof is administered, and the additional therapeutic agent is administered sequentially.

54. The use according to claim 45, wherein the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

55. The use according to claim 45, wherein the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

56. The use according to claim 45, wherein the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

57. The use according to claim 45, wherein the additional therapeutic agent is selected from: or a pharmaceutically acceptable salt thereof.

58. The use according to claim 45, wherein the additional therapeutic agent is selected from: or a pharmaceutically acceptable salt thereof.

59. The use according to claim 45, wherein the additional therapeutic agent is: or a pharmaceutically acceptable salt thereof. The use according to claim 45, wherein the additional therapeutic agent is: or a pharmaceutically acceptable salt thereof.

61. The use according to claim 45, wherein the additional therapeutic agent is selected from: abacavir sulfate, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, emtricitabine, lamivudine, GS-9131, dolutegravir, and cabotegravir.

62. The use according to claim 45, wherein the additional therapeutic agent is selected from: bictegravir, emtricitabine, and GS-9131.

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