Compounds targeting GLP-1 receptor and uses thereof

Abstract

The present disclosure relates to compounds of formula (I) wherein the variables are as defined in the specification, or pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, and / or tautomers thereof, as well as pharmaceutical compositions comprising such compounds. Also described are methods of using such compounds and pharmaceutical compositions to treat GLP-1 related diseases, disorders, and conditions. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to compounds and pharmaceutical compositions for targeting the glucagon-like peptide-1 (GLP-1) receptor and uses thereof. Background of the Invention

[0003] Glucagon-like peptide-1 (GLP-1) is a peptide hormone derived from the proglucagon peptide. It is produced and secreted by intestinal endocrine L cells and certain neurons within the nucleus of the solitary tract in the brainstem upon feeding.

[0004] The most notable action of GLP-1 is its ability to promote insulin secretion in a glucose-dependent manner. When GLP-1 binds to the GLP-1 receptor expressed on pancreatic β cells, the receptor couples with G protein subunits and activates adenylate cyclase, increasing cAMP produced from ATP. Subsequently, the activation of secondary pathways, including PKA and Epac2, alters the activity of ion channels, leading to an increase in cytoplasmic Ca 2+ levels and enhancing the exocytosis of insulin-containing granules.

[0005] The GLP-1R is a class B G protein-coupled receptor (GPCR) with seven transmembrane domains. Class B GPCRs, including the GLP-1R, are activated by endogenous peptide hormones, and the development of small molecule agonists for these receptors has proven particularly challenging. Extensive previous efforts across the pharmaceutical industry have generally failed to discover potent small molecule agonists of the GLP-1R. Accordingly, there is a need for better oral small molecule agonists of the GLP-1R. Summary of the Invention

[0007] The present disclosure relates to compounds and pharmaceutical compositions for targeting the glucagon-like peptide-1 (GLP-1) receptor and uses thereof. In some embodiments, the compounds include the structure of any one of formulas (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb). In additional embodiments, the compounds include the structures provided in Table 1 or Table 3c. Further details are as follows.

[0008] Definitions

[0009] As used in the present disclosure, the articles “a” and “an” refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, “an element” means one element or more than one element.

[0010] As used herein, the term “about” means ±10% of any recited value. As used herein, the term modifies any recited value, range of values, or endpoints of one or more ranges.

[0011] "Aliphatic" refers to a hydrocarbon group having at least 1 to 50 carbon atoms (C 1-50 ), such as 1 to 25 carbon atoms (C 1-25 ), or 1 to 10 carbon atoms (C 1-10 ), and the hydrocarbon group includes alkanes (or alkyl groups, such as those described herein), alkenes (or alkenyl groups), alkynes (or alkynyl groups), including their cyclic forms, and the hydrocarbon group also includes straight-chain and branched-chain arrangements and all stereoisomers and positional isomers. Such hydrocarbons may be unsubstituted or substituted with one or more groups (e.g., the groups described herein for alkyl groups).

[0012] "Alkenyl" refers to an optionally substituted C 2-24 hydrocarbon group having one or more double bonds. The alkenyl group may be cyclic (such as C 3-24 cycloalkenyl) or acyclic. The alkenyl group may also be substituted or unsubstituted. For example, the alkenyl group may be substituted with one or more of the substituents described herein for alkyl groups. Non-limiting unsubstituted alkenyl groups include allyl and vinyl. In some embodiments, the unsubstituted alkenyl group is C 2-6 , C 2-8 , C 2-10 , C 2-12 , C 2-16 , C 2-18 , C 2-20 , C 2-24 , C 3-8 , C 3-10 , C 3-12 , C 3-16 , C 3-18 , C 3-20 or C 3-24 alkenyl. Non-limiting examples of alkenyl groups include vinyl (-CH=CH 2 ), 1-propenyl (-CH=CHCH 3 ), allyl or 2-propenyl (-CH 2 -CH=CH 2 ), 1-butenyl (-CH=CHCH 2 CH 3 ), 2-butenyl (-CH 2 CH=CHCH 3 ), 3-butenyl (-CH 2 CH 2 CH=CH 2 ), 2-butene-1,3-diyl (=CH-CH=CHCH 3 ), etc.

[0013] "Alkoxy" means -OR, where R is an optionally substituted aliphatic group or alkyl group as described herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, trihaloalkoxy (e.g., trifluoromethoxy), and the like. The alkoxy group can be substituted or unsubstituted. For example, the alkoxy group can be substituted with one or more substituents described herein for alkyl groups. Non-limiting examples of unsubstituted alkoxy groups include C 1-3 、C 1-6 、C 1-12 、C 1-16 、C 1-18 、C 1-20 or C 1-24 alkoxy groups.

[0014] "Alkyl" and the prefix "alk-" refer to branched or straight-chain saturated hydrocarbon groups having 1 to 24 carbon atoms, such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr), cyclopropyl, n-butyl (n-Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), n-pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more of the following groups: alkenyl, alkoxy, alkynyl, amino, aryl, formyl (such as, -C(O)H), carboxyl (such as, -CO 2 H), cyano (such as, -CN), halogen, nitro (such as, -NO 2 ), oxo (such as, =O), and the like. In another example, the alkyl group can be substituted with one, two, three, or four (in the case of alkyl groups having two or more carbon atoms) substituents independently selected from the group consisting of: (1) C 1-6 alkoxy (such as, -O-R, where R is C 1-6 alkyl); (2) C 1-6 alkylsulfinyl (such as, -S(O)-R, where R is C 1-6 alkyl); (3) C 1-6 alkylsulfonyl (such as, -SO 2 -R, where R is C 1-6 alkyl); (4) amide (such as, -NHCOR 1 , where R 1 is selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaliphatic, aromatic groups as defined herein, or any combination thereof); (5) aryl (such as, C 6-18(aryl); (6) arylalkoxy (such as, -O-L-R, where L is C 1-6 alkylene and R is C 6-18 aryl); (7) arylacyl (such as, -C(O)-R, where R is C 6-18 aryl); (8) azido (such as, -N 3 ); (9) cyano (such as, -CN); (10) aldehyde group (such as, -C(O)H); (11) C 3-8 cycloalkyl; (12) halogen; (13) heterocyclic group (such as, as defined herein, for example, a 5-, 6- or 7-membered ring containing one, two, three or four non-carbon heteroatoms); (14) heterocyclic oxy group (such as, -O-R, where R is a heterocyclic group as defined herein); (15) heterocyclic acyl group (such as, -C(O)-R, where R is a heterocyclic group as defined herein); (16) hydroxy group (such as, -OH); (17) N-protected amino group; (18) nitro group (such as, -NO 2 ); (19) oxo (such as, =O); (20) C 1-6 alkylthio group (such as, -S-R, where R is alkyl); (21) thiol (such as, -SH); (22) -CO 2 R 1 , where R 1 is selected from the group consisting of: (a) hydrogen, (b) C 1-6 alkyl, (c) C 6-18 aryl, and (d) C 1-6 alkyl-C 6-18 aryl (such as, -L-R, where L is C 1-6 alkylene and R is C 6-18 aryl); (23) -C(O)NR 1 R 2 , where R 1 and R 2 are each independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 alkyl, (c) C 6-18 aryl, and (d) C 1-6 alkyl-C 6-18 aryl (such as, -L-R, where L is C 1-6 alkylene and R is C 6-18 aryl); (24) -SO 2 R 1 , where R 1 is selected from the group consisting of: (a) C 1-6 alkyl, (b) C 6-18 aryl, and (c) C 1-6 alkyl-C 6-18 aryl (such as, -L-R, where L is C1-6 an alkylene group and R is C 6-18 aryl); (25) -SO 2 NR 1 R 2 , wherein R 1 and R 2 are each independently selected from the group consisting of: (a) hydrogen, (b) C 1-6 alkyl, (c) C 6-18 aryl, and (d) C 1-6 alkyl-C 6-18 aryl (such as, -L-R, wherein L is C 1-6 alkylene and R is C 6-18 aryl); (26) -NR 1 R 2 , wherein R 1 and R 2 are each independently selected from the group consisting of: (a) hydrogen, (b) an N-protecting group, (c) C 1-6 alkyl, (d) C 2-6 alkenyl, (e) C 2-6 alkynyl, (f) C 6-18 aryl, (g) C 1-6 alkyl-C 6-18 aryl (such as, -L-R, wherein L is C 1-6 alkylene and R is C 6-18 aryl), (h) C 3-8 cycloalkyl, and (i) C 1-6 alkyl-C 3-8 cycloalkyl (such as, -L-R, wherein L is C 1-6 alkylene and R is C 3-8 cycloalkyl), provided that in one embodiment, there are no two groups attached to the nitrogen atom through a carbonyl or sulfonyl group; and (27) one or more isotopes, such as one or more isotopes of hydrogen, carbon, nitrogen, oxygen, and / or fluorine (such as 3 H, 2 H, 11 C, 13 C, 14 C, 15 N, 18 O, and / or 18 F). In some embodiments, the substituents may include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8A halo cycloalkyl group, or a combination of any of these. The alkyl group may be a primary, secondary or tertiary alkyl group substituted with one or more substituents (such as one or more halogens or alkoxy groups). In some embodiments, the unsubstituted alkyl group is C 1-3 - 1-4 - 1-6 - 1-8 - 1-10 - 1-12 - 1-16 - 1-18 - 1-20 - 1-24 - 2-6 - 2-8 - 2-10 - 2-12 - 2-16 - 2-18 - 2-20 - 2-24 - 3-8 - 3-10 - 3-12 - 3-16 - 3-18 - 3-20 or C 3-24 alkyl group.

[0015] "Alkylene" refers to a polyvalent (such as divalent) form of an aliphatic group or alkyl group as described herein. Non-limiting examples of alkylene include methylene, ethylene, propylene, butylene, etc. In some embodiments, the alkylene is C 1-3 - 1-4 - 1-6 - 1-12 - 1-16 - 1-18 - 1-20 - 1-24 - 2-3 - 2-6 - 2-12 - 2-16 - 2-18 - 2-20 or C 2-24 alkylene. The alkylene may be branched or straight-chain. The alkylene may also be substituted or unsubstituted. For example, the alkylene may be substituted with one or more substituents described herein for alkyl groups.

[0016] "Alkynyl" refers to an optionally substituted C 2-24Alkynyl. The alkynyl group can be cyclic or acyclic, and examples thereof are ethynyl, 1-propynyl, etc. The alkynyl group can also be substituted or unsubstituted. For example, the alkynyl group can be substituted with one or more of the substituents described herein for the alkyl group. Non-limiting unsubstituted alkynyl groups include C 2-8 alkynyl, C 2-6 alkynyl, C 2-5 alkynyl, C 2-4 alkynyl, or C 2-3 alkynyl. Non-limiting examples of the alkynyl group include ethynyl (-C≡CH), 1-propynyl (-C≡CCH 3 ), 2-propynyl or propargyl (-CH 2 C≡CH), 1-butynyl (-C≡CCH 2 CH 3 ), 2-butynyl (-CH 2 C≡CCH 3 ), 3-butynyl (-CH 2 CH 2 C≡CH), etc. In some embodiments, the unsubstituted alkynyl group is C 2-6 , C 2-8 , C 2-10 , C 2-12 , C 2-16 , C 2-18 , C 2-20 , C 2-24 , C 3-8 , C 3-10 , C 3-12 , C 3-16 , C 3-18 , C 3-20 or C 3-24 alkynyl.

[0017] "Amino" refers to -NR N1 R N2 group, -NR N1 - group, or a compound having such a group, wherein R N1 and R N2 are each independently H, optionally substituted aliphatic, alkyl, heteroaliphatic, heteroalkyl, aromatic or aryl; or wherein R N1 and R N2 form a heterocyclic group as defined herein with the nitrogen atom to which they are each attached.

[0018] "Aromatic" refers to a cyclic conjugated group or moiety which, unless otherwise specified, has from 5 to 15 ring atoms and has a single ring (such as phenyl) or multiple fused rings in which at least one ring is aromatic (such as naphthyl, indolyl or pyrazolopyridinyl); that is, at least one ring, and optionally multiple fused rings, have a continuous delocalized π - electron system. Generally, the number of out - of - plane π - electrons conforms to Hückel's rule (4n + 2). The point of attachment to the parent structure is typically through the aromatic portion of the fused ring system.

[0019] "Aryl" refers to an aromatic carbocyclic group that contains from at least 5 to 18 carbon atoms (C 5-18 ), for example 5 to 10 carbon atoms (C 5-10 ), which has a single ring or multiple fused rings, where the fused rings may or may not be aromatic, provided that the point of attachment to the remaining positions of the compounds disclosed herein is through an atom of the aromatic carbocyclic group. An aryl group may be substituted with one or more groups other than hydrogen (such as alkyl and the substituent groups described herein for alkyl). Non - limiting examples of aryl groups include, but are not limited to, naphthalene, phenyl, biphenyl, phenoxyphenyl, etc. An aryl group may be substituted with one, two, three, four or five of the substituent groups provided herein for alkyl. In a particular embodiment, an unsubstituted aryl group is C 6-18 , C 6-14 , C 6-12 or C 6-10 aryl group.

[0020] "Carbonyl" refers to the - C(O)- group, which may also be represented as >C═O or - CO - group.

[0021] "Cycloaliphatic" refers to an aliphatic group as defined herein that is cyclic.

[0022] "Cycloalkyl" means a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group having from three to eight carbon atoms, unless otherwise specified, and examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Cycloalkyl can include fused / bridged forms, such as bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl can also include spirocyclic rings (such as spiro bicyclic rings where the two rings are connected by only one atom). Non-limiting examples of spirocyclic cycloalkyl include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, etc. Cycloalkyl can also be substituted or unsubstituted. For example, cycloalkyl can be substituted with one or more of the following groups, which include those described herein for alkyl.

[0023] "Cycloheteroaliphatic" means a heteroaliphatic group as defined herein which is cyclic.

[0024] "Halogen" means F, Cl, Br or I.

[0025] "Haloaliphatic" means an aliphatic group as defined herein which is substituted with one or more halogens.

[0026] "Haloalkoxy" means an alkoxy group as defined herein which is substituted with one or more halogens.

[0027] "Haloalkyl" means an alkyl group as defined herein which is substituted with one or more halogens. Non-limiting examples include monofluoromethyl, difluoromethyl, trifluoromethyl, fluorochloromethyl, difluorochloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, monochloromethyl, dichloromethyl, chloroethyl, trichloroethyl, monobromomethyl, monoiodomethyl, etc.

[0028] "Halocycloalkyl" means a cycloalkyl group as defined herein which is substituted with one or more halogens.

[0029] "Haloheteroaliphatic" means a heteroaliphatic as defined herein where one or more hydrogen atoms (e.g., 1 to 10 hydrogen atoms) are independently replaced by a halogen atom (e.g., fluorine, bromine, chlorine or iodine).

[0030] "Heteroaliphatic" refers to an aliphatic group as defined herein, said group containing from at least 1 heteroatom to 20 heteroatoms, such as from 1 to 15 heteroatoms, or from 1 to 5 heteroatoms, said heteroatoms being selected from, but not limited to, boron, halogen, nitrogen, oxygen, phosphorus, selenium, silicon, sulfur, and (if applicable) their oxidized forms within said group.

[0031] "Heteroalkyl", "heteroalkenyl", and "heteroalkynyl" each refer to an alkyl, alkenyl, or alkynyl (which may be branched, straight-chain, or cyclic) as defined herein, which contains from at least 1 heteroatom to 20 heteroatoms, such as from 1 to 15 heteroatoms, or from 1 to 5 heteroatoms, said heteroatoms being selected from, but not limited to, boron, halogen, nitrogen (such as as present in an imine), oxygen, phosphorus, selenium, silicon, sulfur, and (if applicable) their oxidized forms within said group.

[0032] "Heteroaromatic" refers to an aromatic group as defined herein, said group containing from at least 1 heteroatom to 20 heteroatoms, such as from 1 to 15 heteroatoms, or from 1 to 5 heteroatoms, said heteroatoms being selected from, but not limited to, boron, nitrogen, oxygen, phosphorus, selenium, silicon, sulfur, and their oxidized forms within said group.

[0033] "Heteroaryl" refers to an aromatic group which contains from at least 1 heteroatom to 6 heteroatoms, such as from 1 to 4 heteroatoms, said heteroatoms being selected from, but not limited to, boron, nitrogen, oxygen, phosphorus, selenium, silicon, sulfur, and their oxidized forms within said group. Such heteroaryl groups may have a single ring or multiple fused rings, where the fused rings may or may not be aromatic or may contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. The heteroaryl group may be substituted by one or more groups other than hydrogen (such as alkyl, and the substituents described herein for alkyl). Non-limiting examples of heteroaryl include the aromatic subset within the heterocyclic groups as defined herein, i.e., they contain 4n+2 π-electrons within a single or multiple cyclic ring systems.

[0034] "Heterocyclic group" refers to a 3-, 4-, 5-, 6- or 7-membered ring (such as, a 5-, 6- or 7-membered ring), unless otherwise specified, the ring contains one, two, three or four non-carbon heteroatoms (such as, independently selected from the group consisting of: nitrogen, oxygen, phosphorus, selenium, silicon, or sulfur). A 3-membered ring has 0 to 1 double bonds, a 4- and 5-membered ring has zero to two double bonds, and a 6- and 7-membered ring has zero to three double bonds. The term "heterocyclic group" also includes bicyclic, tricyclic, tetracyclic, or other polycyclic groups. Heterocycles include acridinyl, adeninyl, lumazinyl, azatricyclodecanyl, azabenzimidazolyl, azabicyclononyl, azepanyl, azocanyl, azacyclononyl, azahypoxanthinyl, azaindazolyl, azaindolyl, azecinyl, azepanyl, aza epinyl, azetidinyl, azetyl, aziridinyl, azirinyl, azocanyl, azocinyl, azonanyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzodiazocinyl, benzodihydrofuranyl, benzodioxepinyl, benzodioxinyl, benzodioxanyl, benzodioxocinyl, benzodioxolyl, benzodithiepinyl, benzodithiinyl, benzodioxocinyl, benzofuranyl, benzophenazinyl, benzopyranonyl, benzopyranyl, benzopyrenyl, benzopyronyl, benzoquinolinyl, benzoquinazinyl, benzothiadiazinyl, benzothiadiazolyl, benzothiazinyl , benzothiazocinyl, benzothiazolyl, benzothiophenyl, benzothiophenyl, benzothiazinone, benzothiazinyl, benzothiopyranyl, benzothiopyronyl, benzotriazinyl ​​groups, benzotriazinonyl groups, benzotriazinyl groups, benzotriazolyl groups, benzoxathiinyl groups, benzotrioxepinyl groups, benzoxadiazepinyl groups, benzoxathiazepinyl groups, benzoxathiepinyl groups, benzoxathiocinyl groups, benzoxazepinyl groups, benzoxazinyl groups, benzoxazocinyl groups, benzoxazolinone groups, benzoxazolinyl groups, benzoxazolyl groups, benzylsultamyl groups, benzylsultimyl groups, bipyrazinyl groups, bipyridyl groups, carbazolyl groups (e.g., 4H-carbazolyl groups), carbolinyl groups (such as, β-carbolinyl groups), chromanonyl groups, chromanyl groups, chromenyl groups, cinnolinyl groups, coumarinyl groups, cytidyl groups, cytosyl groups, decahydroisoquinolinyl groups, decahydroquinolinyl groups, diazabicyclooctyl groups, diazetyl groups, diaziridinethionyl groups, diaziridinonyl groups, diaziridinyl groups (diaziridinyl groups), diazirene groups, dibenzoisoquinolinyl groups, dibenzoacridinyl groups, dibenzocarbazolyl groups, dibenzofuranyl groups, dibenzophenazinyl groups, dibenzopyranonyl groups, dibenzopyranonyl groups (xanthonyl groups), dibenzoquinoxalinyl groups, dibenzothiazepinyl groups, dibenzothiophenyl groups, dibenzothiophenyl groups, dibenzooxepinyl groups, dihydroazepinyl groups groups, benzoxathiazepinyl groups, benzoxathiepinyl groups, benzoxathiocinyl groups, benzoxazepinyl groups, benzoxazinyl groups, benzoxazocinyl groups, benzoxazolinone groups, benzoxazolinyl groups, benzoxazolyl groups, benzylsultamyl groups, benzylsultimyl groups, bipyrazinyl groups, bipyridyl groups, carbazolyl groups (e.g., 4H-carbazolyl groups), carbolinyl groups (such as, β-carbolinyl groups), chromanonyl groups, chromanyl groups, chromenyl groups, cinnolinyl groups, coumarinyl groups, cytidyl groups, cytosyl groups, decahydroisoquinolinyl groups, decahydroquinolinyl groups, diazabicyclooctyl groups, diazetyl groups, diaziridinethionyl groups, diaziridinonyl groups, diaziridinyl groups (diaziridinyl groups), diazirene groups, dibenzoisoquinolinyl groups, dibenzoacridinyl groups, dibenzocarbazolyl groups, dibenzofuranyl groups, dibenzophenazinyl groups, dibenzopyranonyl groups, dibenzopyranonyl groups (xanthonyl groups), dibenzoquinoxalinyl groups, dibenzothiazepinyl groups, dibenzothiophenyl groups, dibenzothiophenyl groups, dibenzooxepinyl groups, dihydroazepinyl base, dihydroazetidinyl, dihydrofuranyl, dihydrofuryl, dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl, dihydropyridyl, dihydroquinolinyl, dihydrothienyl, dihydroindolyl, dioxolanyl, dioxazinyl, dioxindolyl, dioxiranyl, dioxenyl, dioxiny, dioxobenzofuranyl, dioxolyl, dioxotetrahydrofuranyl, dioxothiomorpholinyl, dithianyl, dithiazolyl, dithienyl, dithiinyl, furanyl, furazanyl, furoyl, furyl, guanine, homopiperazinyl, homopiperidinyl, hypoxanthine, hydantoinyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl (e.g., 1H-indazolyl), indolyl, indolinyl, indolizinyl, indolyl (e.g., 1H-indolyl or 3H-indolyl), isatinyl, isatyl, isobenzofuranyl, isochromanyl, isochromenyl, isoindazolyl, isoindolinyl, isoindolyl, isopyrazolinyl, isopyrazolyl, isoxazolidinyl, isoxazolyl, isoquinolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthylindazolyl, naphthylindolyl, naphthiridinyl, naphthopyranyl, naphthothiazolyl, naphthothioxolyl, naphthotriazolyl, naphthoxindolyl, naphthyridinyl, octahydroisoquinolinyl, oxabicycloheptyl, oxauracil, oxadiazolyl, oxazinyl, oxaziridinyl, oxazolidinyl, oxazolidonyl, oxazolinyl, oxazolonyl, oxazolyl, oxacycloheptyl, oxacyclobutanone, oxacyclobutyl, oxetyl, oxtenayloxindolyl, oxiranyl, oxobenzisothiazolyl, oxochromenyl, oxoisoquinolinyl, oxoquinolinyl, oxothiolanyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenothienyl (benzothienyl), phenoxathiinyl, phenoxazinyl, phthalazinyl, phthalazonyl, phthalidyl, phthalimidinyl, piperazinyl, piperidinyl, piperidone (e.g., 4-piperidone), pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyrimidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyrazinyl, pyridopyrimidinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrone, pyrrolidinyl, pyrrolidone (such as, 2-pyrrolidone), pyrroline, pyrrolizidinyl, pyrrolyl (such as, 2H-pyrrolyl), pyrylium, quinazolinyl, quinolinyl, quinazinyl (e.g., 4H-quinazinyl), quinoxalinyl, quinuclidinyl, selenazinyl, selenazolyl, selenophenyl, succinimidyl, sulfolanyl, tetrahydrofuranyl, tetrafuryl, tetrahydroisoquinolinyl, tetraisoquinolyl, tetrahydropyridinyl, piperidinyl, tetrahydropyranyl, tetrahydropyrone, tetrahydroquinolinyl, tetraquinolyl, tetrahydrothienyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, thiadiazinyl (such as, 6H-1,2,5-thiadiazinyl or 2H,6H-1,5,2-thiadiazinyl), thiadiazolyl, thianthrenyl, thianyl, thianaphthenyl, thiaza, base, thiazinyl, thiazolidinedionyl, thiazolidinyl, thiazolyl, thienyl, thiepanyl, thiepinyl, thietanyl, thietyl, thiiranyl, thiocanyl, thiochromanonyl, thiochromanyl, thiochromenyl, thiadiazinyl, thiadiazolyl, thioindoxyl, thiomorpholinyl, thiophenyl, thiopyranyl, thiopyroneyl, thiotriazolyl, thiourazolyl, thioxanyl, thioxolyl, thymidinyl, thyminyl, triazinyl, triazolyl, trithianyl, urazinyl, urazolyl, uretidinyl, uretinyl, uricyl, uridinyl, xanthenyl, xanthinyl, xanthionyl, etc., and their modified forms (such as including one or more oxo and / or amino) and their salts.

[0035] A heterocyclic group may include multiple fused and bridged rings. Non-limiting examples of the fused / bridged heterocyclic group include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. The heterocyclic group may include spiro rings (such as a spiro bicyclic structure where two rings are connected by only one atom). Non-limiting examples of the spiro heterocyclic group include, such as 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, etc. The heterocyclic group may be substituted or unsubstituted. For example, the heterocyclic group may be substituted with one or more substituents as described herein for alkyl groups.

[0036] "Hydroxy" refers to -OH.

[0037] "Oxy" refers to -O-.

[0038] "Sulfinyl" refers to the -S(O)- group.

[0039] "Sulfonyl" means -S(O)- 2 - group.

[0040] "Thio" means -S-.

[0041] As used herein and unless otherwise specified, the term "analogue" refers to a compound that is structurally similar to another compound but slightly different in composition (such as, replacement of an atom by an atom of a different element, or the presence of a specific functional group, or replacement of a functional group by another functional group). Thus, an analogue is a compound that is similar or comparable to a reference compound in terms of function and appearance, rather than structure and origin. Non-limiting examples of analogues include, for example, deuterated analogues, in which one or more hydrogen (H) atoms are replaced by deuterium (D) atoms. Other isotopes may be used. An analogue may include an isotope-labeled compound having one or more isotopes of hydrogen, carbon, nitrogen, oxygen, and / or fluorine (such as 3 H, 2 H, 11 C, 13 C, 14 C, 15 N, 18 O and / or 18 F). In particular, radioactive isotopes that emit radiation upon decay, such as 3 H or 14 C, can be used in pharmaceutical formulations or in vivo topographic tests of compounds. Stable isotopes neither decay, nor change in amount, nor are radioactive, and thus can be used safely. When the atoms constituting the molecule of the compound of the present invention are isotopes, the conversion can be carried out by conventional methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0042] The term "prodrug" means a compound that can be metabolically converted in vivo (e.g., by hydrolysis, oxidation, acidification, etc.) to a compound disclosed herein. In some embodiments, the compound can be provided as a "prodrug" or a protected form, which releases the compound upon administration to an individual. For example, the compound can carry a protecting group that is cleaved by hydrolysis in a body fluid (e.g., blood) to release the active compound, or is oxidized or reduced in a body fluid to release the compound. Thus, a "prodrug" means a compound that can be converted to a bioactive compound of the present invention under physiological conditions or by solvolysis. Accordingly, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention. A prodrug of any compound herein can be prepared by modifying a functional group present in the compound, wherein the modification can be cleaved in a conventional operation or in vivo to release the parent compound described herein. Prodrugs include compounds in which a hydroxyl group, an amino group, or other groups in a compound (such as any compound described herein) are bonded to any group, which can be cleaved when the prodrug of the compound is administered to an individual to form a free hydroxyl group, a free amino group, or a free other group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of an alcohol functional group and acetamide, formamide, and benzamide derivatives of an amine functional group in any compound herein (such as, for example, compounds of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb), or compounds in Table 1 or Table 3c).

[0043] As used herein, unless otherwise indicated, the term "solvate" includes any combination that may be formed by a derivative of the present invention with a suitable inorganic solvent (such as a hydrate) or an organic solvent (e.g., but not limited to an alcohol, a ketone, an ester, etc.).

[0044] As used herein, unless otherwise indicated, the term "stereoisomer" refers to all possible different isomers and conformational forms that a compound of the present invention may have, particularly all possible stereochemical and conformational isomeric forms of the underlying molecular structure, all diastereoisomers, enantiomers, and / or conformers.

[0045] As used herein and unless otherwise stated, the term "tautomer" refers to a compound whose structure is different in the arrangement of atoms, but exists in equilibrium. It should be understood that the compounds disclosed herein can be described as different tautomers. When a compound has tautomeric forms, all tautomeric forms are within the scope of this disclosure, and the naming of the compound does not exclude any tautomer.

[0046] "Salt" refers to a compound or structure in ionic form (such as any of the formulas, compounds, or compositions described herein), which includes cationic or anionic compounds to form a neutral compound or structure. Salts (such as simple salts with binary compounds, double salts, triple salts, etc.) are well known in the art. For example, salts are described in the following documents: Berge S et al., "Pharmaceutical salts," J. Pharm. Sci. 1977 January; 66(1): 1-19; International Union of Pure and Applied Chemistry, "Nomenclature of Inorganic Chemistry," Butterworth & Co. (Publishers) Ltd., London, England, 1971 (2nd ed.); and in "Handbook of Pharmaceutical salts: Properties, Selection, and Use," Wiley-VCH, April 2011 (2nd rev. ed., eds. P.H. Stahl and C.G. Wermuth). Salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure, or salts can be prepared separately by reacting a free basic group with a suitable organic acid (thereby producing an anionic salt) or by reacting an acidic group with a suitable metal or organic salt (thereby producing a cationic salt).Representative anionic salts include acetates, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromides, butyrates, camphorates, camphorsulfonates, chlorides, citrates, cyclopentanepropionates, digluconates, dihydrochlorides, diphosphates, dodecyl sulfates, ethylenediaminetetraacetates, ethylsulfonates, fumarates, glucoheptonates, gluconates, glutamates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrobromides, hydrochlorides, hydroiodides, hydroxyethanesulfonates, hydroxynaphthalenes, iodides, lactates, lactobionates, laurates, dodecyl sulfates, malates, maleates, malonates, mandelates, mesylates / methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, mucates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, polygalacturonates, propionates, salicylates, stearates, basic acetates, succinates, sulfates, tannates, tartrates, theophyllinates, thiocyanates, triethyl iodides, toluenesulfonates, undecanoates, valerates, etc. Representative cationic salts include metal salts, such as alkali or alkaline earth metal salts, such as barium, calcium (such as calcium ethylenediaminetetraacetate), lithium, magnesium, potassium, sodium, etc.; other metal salts, such as aluminum, bismuth, iron, and zinc; and non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, pyridine, etc. Other cationic salts include organic salts, such as chloroprocaine, choline, dibenzylethylenediamine, diethanolamine, ethylenediamine, methylglucamine, and procaine.

[0047] "Pharmaceutically acceptable salts" refers to salts that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment without producing excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio.

[0048] "Pharmaceutically acceptable excipient" means any ingredient other than a compound or structure (such as any formula, compound, or composition described herein) that is non-toxic and non-inflammatory to a patient. Exemplary, non-limiting excipients include: adjuvants, anti-adhesives, antioxidants, binders, carriers, coatings, compression aids, diluents, disintegrants, dispersants, dyes (colorants), wetting agents, emulsifiers, fillers (diluents), film formers or coatings, flavoring agents, fragrances, glidants (flow enhancers), isotonic carriers, lubricants, preservatives, printing inks, solvents, adsorbents, stabilizers, suspending or dispersing agents, surfactants, sweeteners, water of hydration or wetting agents. Any excipient can be selected from those that have been approved as acceptable for use in humans or livestock by, for example, the U.S. Food and Drug Administration or other government agencies. Exemplary excipients include, but are not limited to: ethanol, butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, glycerin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactated Ringer's solution, lactose, magnesium stearate, maltitol, maltose, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, Ringer's solution, shellac, silica, sodium carboxymethylcellulose, sodium chloride injection, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vegetable oil, vitamin A, vitamin E, vitamin C, water, and xylitol.

[0049] As used herein, "administer", "administering", and variations thereof refer to introducing a compound or composition into an individual and include introducing the compound or composition simultaneously or sequentially. "Administer" can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, placebo, and experimental methods. "Administer" also encompasses in vitro and ex vivo therapies. A compound or composition is introduced into an individual by any suitable route (including oral, intralung, intranasal, parenteral (intravenous, intramuscular, intraperitoneal, or subcutaneous), rectal, intralymphatic, or topical routes). Administration includes self-administration and administration by another person. Administration can be effected by any suitable route. A suitable route of administration enables the compound or composition to exhibit its intended function.

[0050] As used herein, the terms "individual", "person", and "patient" are used interchangeably herein and refer to any animal in need of diagnosis, treatment, or therapy, particularly a human. In some embodiments, the individual is a mammal (such as a human individual). In some embodiments, the individual is a non-human mammal (such as a mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon).

[0051] As used herein, the term "therapeutic effect" refers to the result of treatment that is considered desirable and beneficial. A therapeutic effect can include directly or indirectly preventing, reducing, or eliminating the manifestations of a disease. A therapeutic effect can also include directly or indirectly reducing or eliminating the progression of the manifestations of a disease.

[0052] As used herein, the terms "therapeutically effective amount" and "effective amount" are used interchangeably and refer to the amount of a compound or composition sufficient to provide the desired benefit (such as preventing, precluding, delaying the onset of symptoms, or improving the symptoms of a disease). In a prophylactic or preventive application, an effective dose can be administered to an individual who is predisposed or at risk of developing a disease, disorder, or condition to eliminate or reduce the risk of the disease, disorder, or condition (including the biochemical, histological, and / or behavioral symptoms of the disease, disorder, or condition, its complications, and intermediate pathological phenotypes), mitigate its severity, or delay its onset.

[0053] As used herein, the terms "treat" and / or "treatment" include eliminating, substantially inhibiting, slowing, or reversing the progression of a disorder, disease, or condition, substantially improving the clinical symptoms of a disorder, disease, or condition, or substantially preventing the appearance of the clinical symptoms of a disorder, disease, or condition, to obtain a beneficial or desired clinical outcome. Treatment also refers to accomplishing one or more of the following: (a) reducing the severity of a disorder, disease, or condition; (b) restricting the progression of the characteristic symptoms of the disorder, disease, or condition being treated; (c) restricting the worsening of the characteristic symptoms of the disorder, disease, or condition being treated; (d) restricting the recurrence of a disorder, disease, or condition in an individual who has previously had the disorder, disease, or condition; and (e) restricting the recurrence of symptoms in an individual who has not previously had symptoms of a disorder, disease, or condition. Beneficial or desired clinical outcomes, such as pharmacological and / or physiological effects, include, but are not limited to, preventing the occurrence of a disease, disorder, or condition in an individual who is predisposed to the disease, disorder, or condition but has not yet experienced or manifested symptoms of the disease (prophylactic treatment), alleviating the symptoms of a disease, disorder, or condition, reducing the degree of a disease, disorder, or condition, stabilizing (e.g., not worsening) a disease, disorder, or condition, preventing the spread of a disease, disorder, or condition, delaying or slowing the progression of a disease, disorder, or condition, improving or ameliorating a disease, disorder, or condition, and combinations thereof, and extending survival (compared to the survival expected if not treated).

[0054] Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. Detailed Description of the Invention

[0056] The present disclosure relates to any of the compounds described herein (such as the compounds of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb), or the compounds in Table 1 or Table 3c), as well as their pharmaceutically acceptable salts, their stereoisomers, their analogs, their solvates, their prodrugs, or their tautomers. In some non-limiting examples, the compounds (such as any of the compounds described herein) are GLP-1 receptor agonists.

[0057] The present disclosure relates in part to compounds of formula (I):

[0058]

[0059] or their pharmaceutically acceptable salts, their stereoisomers, their tautomers, their analogs (such as their deuterated analogs), or their solvates, wherein:

[0060] R 1 、R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as optionally substituted C 1-6 alkyl), or optionally substituted alkoxy (such as optionally substituted C 1-6 alkoxy);

[0061] L 1 and L 2 are each independently a linking group;

[0062] X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom, and optionally where a double bond is present between Q and an adjacent carbon atom and / or between Y and Z);

[0063] A is an optionally substituted aryl (such as optionally substituted C 6-10 aryl, for example optionally substituted phenyl) (such as where the optional substituents include halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these);

[0064] B is an optionally substituted heterocyclic group (such as an optionally substituted 5- to 10-membered heterocyclic group, for example an optionally substituted bicyclic 5- to 10-membered heterocyclic group; an optionally substituted 5- to 10-membered heteroaryl group, for example an optionally substituted indole) (such as where B may optionally be substituted by V 1 where V 1 is an optionally substituted heterocyclic group (such as an optionally substituted 5- to 10-membered heterocyclic group));

[0065] C is where

[0066] U 1 is an oxy group (such as -O-), a thio group (such as -S-), a sulfinyl group (such as -S(O)-), a sulfonyl group (such as -S(O) 2 -), an optionally substituted amino group (such as -N(R ua ))-), or an optionally substituted alkylene group (such as an optionally substituted C 1-6 alkylene group);

[0067] U 2 is O, -N(R ua ))- or S;

[0068] n1 and n2 are each independently 0, 1, 2, or 3 (such as where at least one of n1 and n2 is not 0);

[0069] R ua are each independently hydrogen (H), an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), an optionally substituted heterocyclic group (such as an optionally substituted 5- to 10-membered heterocyclic group) (such as where the optional substituents include C 1-6 alkyl, halogen, C 1-6 haloalkyl), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group), an optionally substituted sulfonyl group (such as -S(O) 2 -), or an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl group); and

[0070] R uc are each independently hydrogen (H), hydroxy, an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), an optionally substituted haloalkyl group (such as an optionally substituted C 1-6 haloalkyl group), an optionally substituted alkoxy group (such as an optionally substituted C 1-6(alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein), or an isotope, where one or more R uc are present on the ring to which they are attached, and

[0071] D is an optionally substituted heterocyclic group (such as, an optionally substituted 5-10 membered heterocyclic group, for example an optionally substituted bicyclic 5-10 membered heterocyclic group) (such as, where optional substituents include halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0072] In some embodiments, C is In some embodiments, C is

[0073] This disclosure relates in part to compounds of formula (I) and their pharmaceutically acceptable salts, their stereoisomers, their analogs, their solvates, their prodrugs, or their tautomers:

[0074] Wherein:

[0075] R 1 , R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), or optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy);

[0076] L 1 and L 2 are each independently a linking group;

[0077] X, Y, Z and Q are each independently C or N, and the dashed line represents an optional double bond (such as, where two double bonds are not attached to the same atom, and optionally, where a double bond is present between Q and an adjacent carbon atom and / or between Y and Z);

[0078] A comprises an optionally substituted aryl (such as an optionally substituted C 6-10 aryl, for example an optionally substituted phenyl) (such as where the optional substituents include halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these);

[0079] B comprises an optionally substituted heterocyclic group (such as an optionally substituted 5- to 10-membered heterocyclic group, for example an optionally substituted bicyclic 5- to 10-membered heterocyclic group) (such as where B may optionally be V 1 substituted as described herein);

[0080] C comprises wherein U 1 is oxy (such as -O-), thio (such as -S-), sulfinyl (such as -S(O)-), sulfonyl (such as -S(O) 2 -), an optionally substituted amino (such as -N(R ua ))-, or an optionally substituted alkylene (such as an optionally substituted C 1-6 alkylene); U 2 is O or S; n1 and n2 are each independently 0, 1, 2, or 3 (such as where at least one of n1 and n2 is not 0); R ua are each independently hydrogen (H), an optionally substituted alkyl (such as an optionally substituted C 1-6 alkyl), an optionally substituted alkoxy (such as an optionally substituted C 1-6 alkoxy), or an optionally substituted cycloalkyl (such as an optionally substituted C 3-8 cycloalkyl); and R uc are each independently hydrogen (H), hydroxy, an optionally substituted alkyl (such as an optionally substituted C 1-6 alkyl), an optionally substituted haloalkyl (such as an optionally substituted C 1-6 haloalkyl), an optionally substituted alkoxy (such as an optionally substituted C 1-6 alkoxy), an optionally substituted haloalkoxy (such as an optionally substituted C 1-6 haloalkoxy), an optionally substituted cycloalkyl (such as an optionally substituted C 3-8 cycloalkyl), an optionally substituted halocycloalkyl (such as an optionally substituted C 3-8 halocycloalkyl), amino (such as -NRN1 R N2 , as described herein), or an isotope, where there can be one or more Rs uc present on the ring to which they are attached; and

[0081] D comprises an optionally substituted heterocyclic group (such as, an optionally substituted 5-10 membered heterocyclic group, for example an optionally substituted bicyclic 5-10 membered heterocyclic group) (such as, where the optional substituents include halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0082] The compounds of formula (I) can be prepared by any available method. Scheme I provides a non-limiting general method for preparing the compounds. A, B, C, D, R 1 , R 2 , R 3 , X, Y, Z, Q, L 2 and L 1 can each be any of those described herein. LG represents a leaving group (such as, alkoxy, hydroxy, halogen, etc.).

[0083] Scheme I

[0084]

[0085] Referring to Scheme I, the coupling of reagent I-1 with I-2 under standard coupling conditions can provide the compounds of formula I. For example, when L 1 is -C(=O)-, under amide bond formation conditions, such as, in the presence of a carboxyl activator such as EDCI, DCC, HATU, HBTU, HCTU, PyBOP, DPPA, especially HATU (2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (such as, in a polar aprotic solvent, for example DMF).

[0086] Scheme II provides a non-limiting general method for preparing the compound (I-2'). B, L 1 , U 1 , U 2 , n1, n2 and R ua can each be any of those described herein. LG represents a leaving group (such as, alkoxy, hydroxy, halogen, etc.). I-2' can react with I-1 to provide non-limiting examples of the compounds of formula (I) (such as, compound (I')), where C is or its stereoisomers. The reaction of reagent I-3 with I-2a under basic conditions provides reagent I-2b. Treatment of I-2b with an amine source followed by reaction with a carbonyl equivalent such as carbonyldiimidazole provides reagent I-2’, which is a non-limiting example of reagent I-2. Then, reagent I-1 is coupled with I-2’ under standard coupling conditions, e.g., when L 1 is -C(=O)-, coupling under amide bond-forming conditions, such as in the presence of a carboxyl activator such as HATU (e.g., in a polar aprotic solvent such as DMF), can provide non-limiting examples of compounds encompassed by formula I (such as compound I’). Protecting or deprotecting chemistry can be used as needed. The reagents and compounds can be provided in any available form, such as their stereoisomers, their tautomers, their prodrug forms, their analogs, their salts, and / or their solvates. Accordingly, one or more chiral centers may or may not be present in such reagents and / or compounds. Other synthetic strategies can be used.

[0087] Scheme II

[0088]

[0089] This disclosure relates in part to compounds having the structures of formulae (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb), and their pharmaceutically acceptable salts, their stereoisomers, their analogs, their solvates, their prodrugs, or their tautomers.

[0090] In some embodiments, the compound comprises the structure of formula (IIa):

[0091]

[0092] or its pharmaceutically acceptable salt, its stereoisomer, its analog, its solvate, its prodrug, or its tautomer. R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、L 1 、L 2 、X, Y, Z, Q, W 1 、W 2 、W 3 、W 4 、W 5 、W 6 、W 7 、R wa 、U 1 、U 2 、Rua , R uc , n1, n2, and V 1 Each can be any of those described herein.

[0093] In some embodiments, R 1 , R 2 , and R 3 are each independently hydrogen (H), a halogen, a hydroxyl group, an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), or an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group). In some embodiments, R 1 and R 2 are independently H, an optionally substituted alkyl group, or an optionally substituted alkoxy group. In some embodiments, R 1 and R 2 are independently hydrogen (H) or an optionally substituted alkyl group.

[0094] In some embodiments, R 4 is hydrogen (H), an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group), or an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl group).

[0095] In some embodiments, R 5 , R 6 , and R 7 are each independently hydrogen (H), a halogen, an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), an optionally substituted haloalkyl group (such as an optionally substituted C 1-6 haloalkyl group), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group), an optionally substituted haloalkoxy group (such as an optionally substituted C 1-6 haloalkoxy group), an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl group) or an optionally substituted halocycloalkyl group (such as an optionally substituted C 3-8 halocycloalkyl group) (such as where the optional substituents include one or more of the following: a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C3-8 halocycloalkyl, or any combination thereof).

[0096] In some embodiments, L 1 and L 2 are each independently a linking group.

[0097] In some embodiments, X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom, and optionally where a double bond is present between Q and an adjacent carbon atom and / or between Y and Z).

[0098] In some embodiments, W 1 , W 3 and W 4 are each independently C or N.

[0099] In some embodiments, W 2 is CR wa , NR wa , N, O, or S, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom).

[0100] In some embodiments, W 5 , W 6 and W 7 are each independently CR wa or N.

[0101] In some embodiments, R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as optionally substituted C 1-6 alkyl) (such as where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination thereof).

[0102] In some embodiments, U 1 is -N(R ua ).

[0103] In some embodiments, U 1 is oxy (such as -O-), thio (such as -S-), sulfinyl (such as -S(O)-), sulfonyl (such as -S(O) 2 -), optionally substituted amino (such as -N(R ua)-), or optionally substituted alkylene (such as, optionally substituted C 1-6 alkylene).

[0104] In some embodiments, U 2 is O. In some embodiments, U 2 is S. In some embodiments, U 2 is -N(R ua )-.

[0105] In some embodiments, R ua is independently hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted heterocyclic group (such as, optionally substituted 5- to 10-membered heterocyclic group) (such as, wherein the optional substituents include C 1-6 alkyl, halogen, C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted sulfonyl group (such as, -S(O) 2 -), or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl). In some embodiments, R ua is independently hydrogen (H), C 1-6 alkyl, C 1-6 alkoxy, 5- to 10-membered heterocyclic group, -S(O) 2 -, or C 3-8 cycloalkyl, wherein the C ua alkyl, C 1-6 alkoxy, 5- to 10-membered heterocyclic group, -S(O) 1-6 -, or C 2 cycloalkyl of R 3-8 is each independently optionally substituted by the following groups: halogen, oxo, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-8 cycloalkyl. In some embodiments, R ua is hydrogen. In some embodiments, R ua is unsubstituted 5- to 10-membered heteroaryl. In some embodiments, R ua is unsubstituted 5- to 10-membered heterocyclic group. In some embodiments, R ua is 6-membered heterocyclic group. In some embodiments, R ua is 6-membered heteroaryl, such as pyridyl or pyrimidinyl.

[0106] In some embodiments, R uaEach independently is hydrogen (H), an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl), an optionally substituted alkoxy (such as, an optionally substituted C 1-6 alkoxy), or an optionally substituted cycloalkyl (such as, an optionally substituted C 3-8 cycloalkyl).

[0107] In some embodiments, R uc each independently is hydrogen (H), a hydroxyl group, an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl), an optionally substituted haloalkyl (such as, an optionally substituted C 1-6 haloalkyl), an optionally substituted alkoxy (such as, an optionally substituted C 1-6 alkoxy), an optionally substituted haloalkoxy (such as, an optionally substituted C 1-6 haloalkoxy), an optionally substituted cycloalkyl (such as, an optionally substituted C 3-8 cycloalkyl), an optionally substituted halocycloalkyl (such as, an optionally substituted C 3-8 halocycloalkyl), an amino group (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached.

[0108] In some embodiments, n1 and n2 each independently are 0, 1, 2, or 3 (such as, where at least one of n1 and n2 is not 0).

[0109] In some embodiments, V 1 comprises an optionally substituted heterocyclic group (such as, an optionally substituted heteroaryl).

[0110] In some embodiments, the compound comprises a structure of formula (IIb):

[0111]

[0112] or a pharmaceutically acceptable salt thereof, its stereoisomers, its analogs, its solvates, its prodrugs, or its tautomers. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R La , R Lb , X, Y, Z, Q, W 1 , W2 , W 3 , W 4 , W 5 , W 6 , W 7 , R wa , U 1 , U 2 , R ua , R uc , n1, n2, and V 1 Each can be any of those described herein.

[0113] In some embodiments, R 1 , R 2 , and R 3 are each independently hydrogen (H), a halogen, a hydroxyl group, an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), or an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group). In some embodiments, R 1 and R 2 are independently H, an optionally substituted alkyl group, or an optionally substituted alkoxy group. In some embodiments, R 1 and R 2 are independently hydrogen (H) or an optionally substituted alkyl group.

[0114] In some embodiments, R 4 is hydrogen (H), an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group), or an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl group).

[0115] In some embodiments, R 5 , R 6 , and R 7 are each independently hydrogen (H), a halogen, an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), an optionally substituted haloalkyl group (such as an optionally substituted C 1-6 haloalkyl group), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group), an optionally substituted haloalkoxy group (such as an optionally substituted C 1-6 haloalkoxy group), an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl group), or an optionally substituted halocycloalkyl group (such as an optionally substituted C3-8 (halocycloalkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0116] In some embodiments, R La and R Lb (if present) are each independently hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), or optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), and optionally R La and R Lb together with the nitrogen atom to which they are attached each form an optionally substituted heterocyclic group.

[0117] In some embodiments, X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as, wherein two double bonds are not attached to the same atom, and optionally wherein a double bond is present between Q and an adjacent carbon atom and / or between Y and Z).

[0118] In some embodiments, W 1 , W 3 and W 4 are each independently C or N.

[0119] In some embodiments, W 2 is CR wa , NR wa , N, O, or S, and the dashed line represents an optional double bond (such as, wherein two double bonds are not attached to the same atom).

[0120] In some embodiments, W 5 , W 6 and W 7 are each independently CR wa or N.

[0121] In some embodiments, R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or a combination of any of these).

[0122] In some embodiments, U 1 is an oxy group (such as, -O-), a thio group (such as, -S-), a sulfinyl group (such as, -S(O)-), a sulfonyl group (such as, -S(O) 2 -), an optionally substituted amino group (such as, -N(R ua )-), or an optionally substituted alkylene group (such as an optionally substituted C 1-6 alkylene).

[0123] In some embodiments, U 2 is O. In some embodiments, U 2 is S. In some embodiments, U 2 is -N(R ua ).

[0124] In some embodiments, R ua are each independently hydrogen (H), an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy), or an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl).

[0125] In some embodiments, R uc are each independently hydrogen (H), a hydroxyl group, an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl), an optionally substituted haloalkyl group (such as an optionally substituted C 1-6 haloalkyl), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy), an optionally substituted haloalkoxy group (such as an optionally substituted C 1-6 haloalkoxy), an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl), an optionally substituted halocycloalkyl group (such as an optionally substituted C 3-8 halocycloalkyl), an amino group (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached.

[0126] In some embodiments, n1 and n2 are each independently 0, 1, 2, or 3 (such as where at least one of n1 and n2 is not 0).

[0127] In some embodiments, V 1 comprises an optionally substituted heterocyclic group (such as an optionally substituted heteroaryl).

[0128] In some embodiments, V 1 is an optionally substituted heterocyclic group. In some embodiments, V 1 is a 5- to 10-membered heterocyclic group. In some embodiments, V 1 is In some embodiments, V 1 is In some embodiments, V 1 is

[0129] In some embodiments, the compound comprises a structure of formula (IIc):

[0130]

[0131] or a pharmaceutically acceptable salt thereof, its stereoisomers, its analogs, its solvates, its prodrugs, or its tautomers. R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、X, Y, Z, Q, W 1 、W 2 、W 3 、W 4 、W 5 、W 6 、W 7 、R wa 、U 1 、U 2 、R ua 、R uc 、n1, n2, and V 1 each can be any of those described herein.

[0132] In some embodiments, R 1 、R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, an optionally substituted alkyl (such as an optionally substituted C 1-6 alkyl), or an optionally substituted alkoxy (such as an optionally substituted C 1-6(alkoxy). In some embodiments, R 1 and R 2 are independently H, optionally substituted alkyl, or optionally substituted alkoxy. In some embodiments, R 1 and R 2 are independently hydrogen (H) or optionally substituted alkyl.

[0133] In some embodiments, R 4 is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl).

[0134] In some embodiments, R 5 , R 6 and R 7 are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), or optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl) (such as, where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of any of these).

[0135] In some embodiments, X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as, where two double bonds are not attached to the same atom, and optionally where a double bond is present between Q and an adjacent carbon atom and / or between Y and Z).

[0136] In some embodiments, W 1 , W 3 and W 4 are each independently C or N.

[0137] In some embodiments, W 2 is CR wa , NR wa , N, O, or S, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom).

[0138] In some embodiments, W 5 , W 6 and W 7 are each independently CR wa or N.

[0139] In some embodiments, R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as optionally substituted C 1-6 alkyl) (such as where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0140] In some embodiments, U 1 is oxy (such as, -O-), thio (such as, -S-), sulfinyl (such as, -S(O)-), sulfonyl (such as, -S(O) 2 -), optionally substituted amino (such as, -N(R ua )-), or optionally substituted alkylene (such as optionally substituted C 1-6 alkylene).

[0141] In some embodiments, U 2 is O. In some embodiments, U 2 is S. In some embodiments, U 2 is -N(R ua )-.

[0142] In some embodiments, R ua are each independently hydrogen (H), optionally substituted alkyl (such as optionally substituted C 1-6 alkyl), or optionally substituted alkoxy (such as optionally substituted C 1-6 alkoxy).

[0143] In some embodiments, R ucEach independently is hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached.

[0144] In some embodiments, n1 and n2 are each independently 0, 1, 2, or 3 (such as, where at least one of n1 and n2 is not 0).

[0145] In some embodiments, V 1 comprises an optionally substituted heterocyclic group (such as, optionally substituted heteroaryl).

[0146] In some embodiments, the compound comprises a structure of formula (IIIa):

[0147]

[0148] or a pharmaceutically acceptable salt thereof, its stereoisomers, its analogs, its solvates, its prodrugs, or its tautomers. U 1 , R uc , n1 and V 1 can each be any of those described herein.

[0149] In some embodiments, U 1 is oxy (such as, -O-), thio (such as, -S-), sulfinyl (such as, -S(O)-), sulfonyl (such as, -S(O) 2 -), optionally substituted amino (such as, -N(R ua ))- or optionally substituted alkylene (such as, optionally substituted C 1-6 alkylene).

[0150] In some embodiments, R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached.

[0151] In some embodiments, n1 is 0, 1, 2, or 3.

[0152] In some embodiments, V 1 is an optionally substituted heterocyclic group.

[0153] In some embodiments, the compound comprises a structure of formula (IIIb):

[0154]

[0155] its pharmaceutically acceptable salts, its stereoisomers, its analogs, its solvates, its prodrugs, or its tautomers. R 4 、R 5 、R 6 、R 7 , and R uc each can be any one described herein.

[0156] In some embodiments, R 4 is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl).

[0157] In some embodiments, R 5 、R 6 and R 7 each independently is hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C1-6 (haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) or optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0158] In some embodiments, R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached.

[0159] In some embodiments, the compound comprises a structure of formula (IIIc):

[0160]

[0161] or a pharmaceutically acceptable salt thereof, its stereoisomers, its analogs, its solvates, its prodrugs, or its tautomers. X, Y, Z, Q, W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , W 7 , Rwa and R uc Each may be any of those described herein.

[0162] In some embodiments, X, Y, Z, and Q are each independently C or N, and the dashed lines represent optional double bonds (such as where two double bonds are not attached to the same atom, and optionally where a double bond is present between Q and an adjacent carbon atom and / or between Y and Z).

[0163] In some embodiments, W 1 , W 3 and W 4 are each independently C or N.

[0164] In some embodiments, W 2 is CR wa , NR wa , N, O, or S, and the dashed lines represent optional double bonds (such as where two double bonds are not attached to the same atom).

[0165] In some embodiments, W 5 , W 6 and W 7 are each independently CR wa or N.

[0166] In some embodiments, R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as optionally substituted C 1-6 alkyl) (such as where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0167] In some embodiments, R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as optionally substituted C 3-8cycloalkyl), optionally substituted haloalkyl (such as, optionally substituted C 3-8 haloalkyl), amino (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached.

[0168] In any embodiment herein, R 1 , R 2 and R 3 are each independently hydrogen (H) or optionally substituted alkyl.

[0169] In any embodiment herein, X and Y are each N, Y and Z are each N, or Y and Q are each N.

[0170] In any embodiment herein, X is N, and the first double bond is between Q and the adjacent carbon atom, and the second double bond is between Y and Z.

[0171] In any embodiment herein, Z is N, and the first double bond is between Q and the adjacent carbon atom, and the second double bond is between X and Y.

[0172] In any embodiment herein, Q is N, and the first double bond is between X and the adjacent carbon atom, and the second double bond is between Y and Z.

[0173] In any embodiment herein, L 1 is a carbonyl (such as, -C(O)-), an alkylene (such as, optionally substituted C 1-6 alkylene), a sulfinyl (such as, -S(O)-), or a sulfonyl (such as, -S(O) 2 -).

[0174] In any embodiment herein, L 2 is R La , R Lb and n4 can each be any of those described herein.

[0175] In some embodiments, n4 is 1, 2, or 3, and the dashed line represents an optional double bond (such as, where two double bonds are not attached to the same atom); and R La and R Lb (if present) are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), or optionally substituted alkoxy (such as, optionally substituted C 1-6(alkoxy), and optionally R La and R Lb each, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic group.

[0176] In any embodiment herein, A comprises an optionally substituted C 6-10 aryl, wherein optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, or C 3-8 halocycloalkyl.

[0177] In any embodiment herein, A comprises wherein R 5 , R 6 , and R 7 are each independently hydrogen (H), halogen, an optionally substituted alkyl (such as an optionally substituted C 1-6 alkyl), an optionally substituted haloalkyl (such as an optionally substituted C 1-6 haloalkyl), an optionally substituted alkoxy (such as an optionally substituted C 1-6 alkoxy), an optionally substituted haloalkoxy (such as an optionally substituted C 1-6 haloalkoxy), an optionally substituted cycloalkyl (such as an optionally substituted C 3-8 cycloalkyl) or an optionally substituted halocycloalkyl (such as an optionally substituted C 3-8 halocycloalkyl) (such as wherein optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0178] In some embodiments, A is

[0179] In some embodiments, A is

[0180] In any embodiment herein, A comprises one or more of the following structures:

[0181]

[0182] In some embodiments, B is an optionally substituted heterocyclic group (such as an optionally substituted 5- to 10-membered heterocyclic group, for example an optionally substituted bicyclic 5- to 10-membered heterocyclic group; an optionally substituted 5- to 10-membered heteroaryl group, for example an optionally substituted indole) (such as where B can optionally be substituted by V 1 where V 1 is an optionally substituted heterocyclic group (such as an optionally substituted 5- to 10-membered heterocyclic group). In some embodiments, B is an optionally substituted 5- to 10-membered heteroaryl group, for example an optionally substituted indole). In some embodiments, B is an optionally substituted indole. In some embodiments, B is

[0183] In any of the embodiments herein, B comprises the following structure:

[0184] W 1 -W 7 Each can be any of those described herein.

[0185] In some embodiments, W 1 , W 3 and W 4 are each independently C or N.

[0186] In some embodiments, W 2 is CR wa , NR wa , N, O or S, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom).

[0187] In some embodiments, W 5 , W 6 and W 7 are each independently CR wa or N (such as where b1, b2 and b3 are attached to L 1 , C and V 1 ) in any order or position.

[0188] In some embodiments, R wa (if present) are each independently hydrogen (H), halogen, or an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group) (such as where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C3-8 halocycloalkyl, or any combination of these).

[0189] In any embodiment herein, B comprises one or more of the following structures:

[0190]

[0191] In any embodiment herein, B comprises the following structure:

[0192] W 1 -W 7 and V 1 each can be any of those described herein.

[0193] In some embodiments, W 1 , W 3 and W 4 are each independently C or N.

[0194] In some embodiments, W 2 is CR wa , NR wa , N, O, or S, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom).

[0195] In some embodiments, W 5 , W 6 and W 7 are each independently CR wa or N (such as where b1 and b2 are attached to L 1 and C) in any order or position.

[0196] In some embodiments, R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as optionally substituted C 1-6 alkyl) (such as where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0197] In some embodiments, V 1 comprises an optionally substituted heterocyclic group (such as an optionally substituted heteroaryl).

[0198] In any embodiment herein, B comprises one or more of the following structures:

[0199]

[0200] V 1 can be any of those described herein.

[0201] In some embodiments, V 1 comprises the following structure:

[0202]

[0203] In some embodiments, V a is N or CR vc .

[0204] In some embodiments, V b is NR Vc , O or S.

[0205] In some embodiments, R va and R vc (if present) are each independently hydrogen (H), a halogen, or an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of any of these), and there can be one or more R va present on V 1 .

[0206] In some embodiments, V 1 comprises one or more of the following structures:

[0207] V a and R va -R vc can each be any of those described herein.

[0208] In some embodiments, V a is N or CR vc .

[0209] In some embodiments, R va , R vb and R vc(If present) each independently is hydrogen (H), a halogen, or an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group) (such as, where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0210] In some embodiments, C is In some embodiments, C is In some embodiments, C is In some embodiments, C is In some embodiments, C is In some embodiments, C is In some embodiments, C is In some embodiments, C is

[0211] In some embodiments, C is

[0212]

[0213]

[0214]

[0215] or a stereoisomer thereof.

[0216] In any of the embodiments herein, C comprises the following structure:

[0217] or a stereoisomer thereof. U 1 、U 2 、R uc 、R ua 、n1 and n2 can each be any of those described herein. Any number of R uc (such as 1, 2, 3, 4, 5, 6 or more) can be present to replace the hydrogens within the ring. In some embodiments, one or more R uc can be selected from hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as optionally substituted C 1-6(haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein), isotopes, etc. In some embodiments, one or more R uc can be any substituent described herein (such as the substituents provided herein for alkyl, for example any one of substituents (1) to (27), and optionally substituted aliphatic, optionally substituted heteroaliphatic, etc.).

[0218] In any embodiment herein, C comprises the following structure:

[0219] or its stereoisomers. U 1 , U 2 , R ua , n1 and n2 can each be any one described herein.

[0220] In any embodiment herein, C comprises the following structure: or its stereoisomers. U 1 , n1 and n2 can each be any one described herein.

[0221] In some embodiments, U 1 is optionally substituted C 1-6 alkylene. In some embodiments, the optionally substituted C 1-6 alkylene is -CR Ua R Ub - or -[CR Ua R Ub n3 -, where n3 is 1, 2, or 3, and where R ua and R ub (if present) are each independently hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy).

[0222] In any embodiment herein, C comprises one or more of the following:

[0223] ​

[0224] In some embodiments, D is In some embodiments, D is

[0225] In any of the embodiments herein, D comprises the following structure:

[0226] R 4 , R da , R bd , R dc and R dd each can be any of those described herein.

[0227] In some embodiments, R da , R bd , R dc and R dd each independently is hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy).

[0228] In some embodiments, R 4 is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) (such as, where the optional substituents include halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0229] In any of the embodiments herein, D comprises the following structure:

[0230] R 4 can be any of those described herein.

[0231] In any of the embodiments herein, D comprises one or more of the following structures:

[0232]

[0233] In any embodiment herein, X is N; X and Y are N; Y and Z are N; or Y and W are N.

[0234] In any embodiment herein, W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 is at least one of N or NR wa . In some embodiments, R wa is hydrogen (H), a halogen, or an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl) (such as, where the optional substituents include one or more of the following: a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0235] In any embodiment herein, R 1 is an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl).

[0236] In any embodiment herein, at least one of R 1 , R 2 and R 3 is not H.

[0237] In any embodiment herein, R 4 is C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 alkyl substituted with one or more C 1-6 cycloalkyl, or C 3-8 alkyl substituted with one or more C 1-6 halocycloalkyl.

[0238] In any embodiment herein, each of R 5 , R 6 and R 7 is independently a halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 alkyl substituted with one or more C1-6 alkyl, or C substituted with one or more C 3-8 halocycloalkyl 1-6 alkyl.

[0239] In any embodiment herein, R 6 is halogen (such as, fluorine or chlorine).

[0240] In any embodiment herein, R 5 and R 7 are each independently halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), (such as, where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0241] In any embodiment herein, at least one of R 5 , R 6 and R 7 is not H.

[0242] In any embodiment herein, U 1 is O or methylene (CH 2 ).

[0243] In some embodiments, U 1 is O.

[0244] In any embodiment herein, n1 is 1, and / or n2 is 1.

[0245] In any embodiment herein, U 2 is O, and / or R ua is H or C 1-6 alkyl.

[0246] In some embodiments, U 2 is O.

[0247] In any embodiment herein, V 1 comprises one or more of the following structures:

[0248]

[0249] In some embodiments, V a is N or CR vc .

[0250] In some embodiments, R va , R vb and R vc (if present) are each independently hydrogen (H), a halogen, or an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl) (such as, where the optional substituents include one or more of the following: a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0251] In any of the embodiments herein, V 1 comprises the following structure:

[0252]

[0253] In some embodiments, V a is N or CR vc .

[0254] In some embodiments, R va and R vc (if present) are each independently hydrogen (H), a halogen, or an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl) (such as, where the optional substituents include one or more of the following: a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, or any combination of these), and there can be one or more R va present on V 1 .

[0255] In any of the embodiments herein, V 1 comprises one or more of the following structures:

[0256]

[0257] In some embodiments, V a is N or CR vc .

[0258] In some embodiments, R va , Rvb and R vc (if present) each independently is hydrogen (H), a halogen, or an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group) (such as, where the optional substituents include one or more of the following: a halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0259] In any embodiment herein, R 4 is C 1-6 alkyl (such as methyl), deuterated C 1-6 alkyl (such as deuterated methyl, e.g., CD 3 ), C 3-8 cycloalkyl (such as cyclopropyl), C 3-8 alkyl substituted with one or more C 1-6 cycloalkyl (such as cyclopropylalkyl, including cyclopropylmethyl), C 3-8 halocycloalkyl (such as 1-halocyclopropyl, including 1-fluorocyclopropyl) or C 3-8 alkyl substituted with one or more C 1-6 halocycloalkyl (such as 1-halocyclopropylalkyl, including 1-fluorocyclopropylmethyl).

[0260] In any embodiment herein, R 5 , R 6 , and R 7 each independently is a halogen (such as fluorine or chlorine), C 1-6 alkyl (such as methyl), C 3-8 cycloalkyl (such as cyclopropyl, e.g., C 3-8 cycloalkyl (such as cyclopropyl), C 3-8 alkyl substituted with one or more C 1-6 cycloalkyl (such as cyclopropylalkyl, including cyclopropylmethyl), C 3-8 halocycloalkyl (such as 1-halocyclopropyl, including 1-fluorocyclopropyl) or C 3-8 alkyl substituted with one or more C 1-6 halocycloalkyl (such as 1-halocyclopropylalkyl, including 1-fluorocyclopropylmethyl).

[0261] In any embodiment herein,

[0262] is In some embodiments, X, Y, Z, and Q can be any of those described herein.

[0263] In any embodiment herein,

[0264] is

[0265] This disclosure relates in part to compounds of formula (IV):

[0266]

[0267] or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analogue thereof (such as a deuterated analogue thereof), or a solvate thereof, wherein:

[0268] R 1 、R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, C 1-6 alkyl, or C 1-6 alkoxy;

[0269] R 4 is hydrogen (H), halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, or C 3-8 halocycloalkyl;

[0270] R 5 、R 6 and R 7 are each independently hydrogen (H), halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, or C 3-8 halocycloalkyl;

[0271] X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond;

[0272] W 1 、W 3 and W 4 are each independently C or N;

[0273] W 2 is CR wa 、NR wa, N, O, or S, and the dashed line represents an optional double bond;

[0274] W 5 , W 6 and W 7 Each is independently CR wa or N;

[0275] R wa (if present) are each independently hydrogen (H), halogen, or C 1-6 alkyl;

[0276] C is Optionally wherein C is

[0277] U 1 Yes -O-, -S-, -S(O)-, -S(O) 2 -、-N(R ua )-or-CH 2 -;

[0278] U 2 is O, -N(R ua )- or S; optionally, U 2 is O or S;

[0279] R ua are independently hydrogen (H), C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heterocyclic group, -S(O) 2 - or C 3-8 Cycloalkyl, where R ua C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heterocyclic group, -S(O) 2 - or C 3-8 The cycloalkyl groups are each independently optionally substituted by halogen, oxo, hydroxy, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 3-8 Cycloalkyl;

[0280] R uc are independently hydrogen (H), hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, -NR N1 R N2 or isotopes, which may contain one or more Ruc are present on the ring to which they are attached; wherein R N1 and R N2 are each independently H, C 1-6 aliphatic, C 1-6 alkyl, C 1-6 heteroaliphatic, C 1-6 heteroalkyl, aromatic or aryl; or wherein R N1 and R N2 form a heterocyclic group with the nitrogen atom to which they are attached;

[0281] n1 and n2 are each independently 0, 1, 2, or 3; and

[0282] V 1 is wherein:

[0283] V a is N or CR vc and

[0284] R va 、R vb and R vc (if present) are each independently hydrogen (H), halogen, or C 1-6 alkyl.

[0285] In some embodiments, the compound of formula (IV) is a compound of formula (IVa):

[0286]

[0287] or a pharmaceutically acceptable salt thereof, its stereoisomers, its tautomers, its analogs (such as its deuterated analogs) or its solvates.

[0288] In some embodiments, the compound is a compound of formula (IVa), wherein C is and V 1 is In some embodiments, C is and V 1 is In some embodiments, C is V 1 is and U 1 is -N(R ua )-. In some embodiments, and in combination with the embodiments above or below, C is U 1 is -N(R ua )-, and U 2 is O. In some embodiments, and in combination with the embodiments above or below, U1 is N(R ua )-and R ua is a substituted or unsubstituted 5- or 6-membered heteroaryl. In some embodiments, and in combination with the embodiments above or below, U 1 is N(R ua )-and R ua is an unsubstituted 5- or 6-membered heteroaryl. In some embodiments, and in combination with the embodiments above or below, U 1 is N(R ua )-and R ua is an unsubstituted 6-membered heteroaryl (such as, pyridine or pyrimidine). In some embodiments, and in combination with the embodiments above or below, V 1 is In some embodiments, and in combination with the embodiments above or below, R 5 , R 6 and R 7 are each independently halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, or C 3-8 halocycloalkyl. In some embodiments, and in combination with the embodiments above or below, R 6 is halogen (such as, fluorine).

[0289] In some embodiments, the compound of formula (IV) is a compound of formula (IVb)

[0290]

[0291] or a pharmaceutically acceptable salt thereof, its stereoisomers, its tautomers, its analogs (such as, its deuterated analogs) or its solvates.

[0292] In some embodiments, R 4 is -CH 3 .

[0293] In some embodiments, R 5 and R 7 are each -CH 3 .

[0294] In some embodiments, R 6 is halogen.

[0295] This disclosure relates in part to compounds having the structures in Table 1, their pharmaceutically acceptable salts, their stereoisomers, their analogs, their solvates, their prodrugs, or their tautomers. In some embodiments, the compound is a compound having the structure in Table 1 or a pharmaceutically acceptable salt thereof.

[0296] Table 1: Non-limiting compounds

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323] This disclosure relates in part to compounds having the structures in Table 3c, their pharmaceutically acceptable salts, their stereoisomers, their analogs, their solvates, their prodrugs, or their tautomers. In some embodiments, the compound is a compound having the structure in Table 3c or a pharmaceutically acceptable salt thereof.

[0324] Table 3c: Non-limiting compounds

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342] In some embodiments, a compound (such as any compound described herein, e.g., a compound of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb), or a compound in Table 1 or Table 3c) exhibits GLP-1 agonist activity (such as measured by an EC 50 value, where such activity can constitute potent GLP-1 agonist activity). In some embodiments, the GLP-1 agonist activity is greater than 0 nM. In some embodiments, the GLP-1 agonist activity is less than 20 nM. In some embodiments, the GLP-1 agonist activity is greater than 20 nM and less than 200 nM. In some embodiments, the GLP-1 agonist activity is greater than 200 nM. In some embodiments, the GLP-1 agonist activity is provided with reference to human GLP-1 (such as UniProt Ref. No. P01275, proglucagon, the preprocessed form of GLP-1) or the human GLP-1 receptor (such as UniProt Ref. No. P43220).

[0343] In some embodiments, a compound (such as any compound described herein, e.g., a compound of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb), or a compound in Table 1 or Table 3c) modulates GLP-1 activity. In some embodiments, a compound (such as any compound described herein, e.g., a compound of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb), or a compound in Table 1 or Table 3c) modulates (such as activates or stimulates) the GLP-1 receptor (such as the human GLP-1 receptor).

[0344] Pharmaceutical compositions

[0345] The compounds of the present invention (such as, for example, compounds of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb), or compounds in Table 1 or Table 3c) can be provided in the form of a pharmaceutical composition containing one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the structure of any one of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb), or the structure provided in Table 1 or Table 3c, and its pharmaceutically acceptable salts, its stereoisomers, its analogs, its solvates, its prodrugs, or its tautomers, and one or more pharmaceutically acceptable excipients.

[0346] The composition can be administered by various routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can include oral, topical (such as transdermal, transepidermal, ophthalmic, and transmucosal, including intranasal, vaginal, and rectal delivery), pulmonary (such as by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), or parenteral (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, intracranial, intrathecal, intratumoral, or intraventricular delivery) modes.

[0347] The pharmaceutical composition can contain any therapeutically effective amount of one or more compounds for the disease, disorder, or condition to be treated.

[0348] In some embodiments, the compounds herein (such as including any of the structures of Formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb) or the structures provided in Table 1 or Table 3c, and their pharmaceutically acceptable salts, their stereoisomers, their analogs, their solvates, their prodrugs, or their tautomers) can be formulated in a composition administered in a certain dosage (such as in a single dose, in separate doses, or in combined doses).

[0349] Method of treatment

[0350] The compounds and compositions herein can be used in any available method. In any embodiment herein, the method can include administering (such as to an individual in need) the compounds herein (such as including any of the structures of Formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb) or the structures provided in Table 1 or Table 3c and their pharmaceutically acceptable salts, their stereoisomers, their analogs, their solvates, their prodrugs, or their tautomers) or the compositions herein (such as a pharmaceutical composition containing any of the structures of Formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb) or the structures provided in Table 1 or Table 3c and their pharmaceutically acceptable salts, their stereoisomers, their analogs, their solvates, their prodrugs, or their tautomers, and one or more pharmaceutically acceptable excipients).

[0351] The present invention provides methods for treating GLP-1 related diseases, disorders or conditions. Without wishing to be bound by mechanism, GLP-1 is a peptide hormone that binds to the GLP-1 receptor and promotes insulin secretion. Thus, GLP-1 agonists represent a class of compounds that bind to (such as and activate) the GLP-1 receptor. Such agonists can be used to treat conditions that would benefit from activation of the GLP-1 receptor (such as enhanced insulin release). For example, and without limitation, type 2 diabetes can be caused by insulin resistance or insufficient insulin production, and GLP-1 agonists can be used to treat (either alone or in combination with other therapies).

[0352] Non-limiting examples of diseases, disorders or conditions include one or more of the following: diabetes, obesity, overweight status, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease, congestive heart failure, arrhythmia, diabetic nephropathy, dementia, Parkinson's disease, Alzheimer's disease, and liver diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0353] Non-limiting examples of other diseases, disorders or conditions include one or more of the following: type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), young-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), overweight, weight gain caused by use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, hyperlipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, arteriosclerosis, coronary heart disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, traumatic brain injury, cerebral infarction, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, post-prandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucosetolerance), diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, impaired cognition, dementia, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

[0354] In some embodiments, the present disclosure includes methods for treating or prophylactically treating GLP-1 related diseases, disorders, or conditions, the methods comprising administering to an individual in need an effective amount of a compound herein (such as, including the structure of any one of formulas (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb) or the structures provided in Table 1 or Table 3c and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof) or a composition herein (such as, a compound comprising any one of formulas (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb) or the structures provided in Table 1 or Table 3c and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof, and one or more pharmaceutically acceptable excipients). In some embodiments, the disease, disorder, or condition is any disease, disorder, or condition described herein (such as, diabetes, obesity, overweight, etc.).

[0355] In some embodiments, the present disclosure includes methods for treating or prophylactically treating diabetes in an individual in need thereof, the methods comprising administering to the individual in need thereof an effective amount of a compound of the present disclosure (such as, including the structure of any one of formulas (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa) and (IVb) or the structures provided in Table 1 or Table 3c, and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof) or a composition of the present disclosure (such as, a compound comprising any one of formulas (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa) and (IVb) or the structures provided in Table 1 or Table 3c, and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof, and one or more pharmaceutically acceptable excipients).

[0356] In some embodiments, the present disclosure includes methods for treating or prophylactically treating type 2 diabetes in an individual in need thereof, the methods comprising administering to the individual in need thereof an effective amount of a compound of the present disclosure (such as, including the structure of any one of formulas (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa) and (IVb) or the structures provided in Table 1 or Table 3c, and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof) or a composition of the present disclosure (such as, a compound comprising any one of formulas (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa) and (IVb) or the structures provided in Table 1 or Table 3c, and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof, and one or more pharmaceutically acceptable excipients).

[0357] In some embodiments, the present disclosure includes methods of treating or prophylactically treating obesity or overweight in an individual in need thereof, the methods comprising administering to the individual in need thereof an effective amount of a compound of the present disclosure (such as, including any one of the structures of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa) and (IVb) or the structures provided in Table 1 or Table 3c and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof) or a composition of the present disclosure (such as, a compound comprising any one of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa) and (IVb) or the structures provided in Table 1 or Table 3c and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof, and one or more pharmaceutically acceptable excipients).

[0358] In some embodiments, the present disclosure includes methods of modulating insulin levels in an individual in need of such modulation, the methods comprising administering to the individual in need thereof an effective amount of a compound of the present disclosure (such as, including any one of the structures of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa) and (IVb) or the structures provided in Table 1 or Table 3c and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof) or a composition of the present disclosure (such as, a compound comprising any one of formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa) and (IVb) or the structures provided in Table 1 or Table 3c and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof, and one or more pharmaceutically acceptable excipients).

[0359] In some embodiments, the present disclosure includes methods of modulating glucose levels in an individual in need of such modulation, the methods comprising administering to the individual in need an effective amount of a compound of the present disclosure (such as, including the structure of any one of Formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb) or the structures provided in Table 1 or Table 3c and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof) or a composition of the present disclosure (such as, a compound comprising any one of Formula (I), (IIa)-(IIc), (IIIa)-(IIIc), (IV), (IVa), and (IVb) or the structures provided in Table 1 or Table 3c and pharmaceutically acceptable salts thereof, stereoisomers thereof, analogs thereof, solvates thereof, prodrugs thereof, or tautomers thereof, and one or more pharmaceutically acceptable excipients).

[0360] In any of the embodiments herein, the method may further comprise administering to the individual an additional therapy or therapeutic agent. In some embodiments, the additional therapy or therapeutic agent may be an anti-diabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an anti-emetic agent, an active agent for treating non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, diet monitoring, physical activity, or a combination thereof.

[0361] In some embodiments, the compounds described herein (e.g., compound C-12 or C-22) exhibit improved pharmacokinetics in an individual, such as a longer half-life, higher exposure, lower clearance, and / or better bioavailability. In some embodiments, the compounds described herein exhibit improved absorption characteristics in an individual. In some embodiments, the compounds described herein also exhibit improved solubility (compared to orforglipron), improved weight loss, and blood glucose lowering effects.

[0362] Biological assays

[0363] The biological activities of the compounds of the present disclosure can be evaluated using methods and assays known in the art. Exemplary methods are described in the Examples, such as the GLP-1R cAMP assay.

[0364] Enumerated embodiments

[0365] Enumerated embodiment 1. A compound of Formula (I):

[0366]

[0367] or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analog thereof (such as, a deuterated analog thereof), or a solvate thereof, wherein:

[0368] R 1 , R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 Alkoxy);

[0369] L 1 and L 2 each independently is a linker;

[0370] X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom, and optionally where a double bond exists between Q and an adjacent carbon atom and / or between Y and Z);

[0371] A includes optionally substituted aryl (such as optionally substituted C 6-10 Aryl, for example optionally substituted phenyl) (such as, wherein the optional substituents include halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these);

[0372] B comprises an optionally substituted heterocyclyl (such as an optionally substituted 5-10 membered heterocyclyl, for example an optionally substituted bicyclic 5-10 membered heterocyclyl) (such as, wherein B may be optionally replaced by V 1 Replacement, as described herein);

[0373] C contains Among them U 1 is oxy (such as, -O-), thio (such as, -S-), sulfinyl (such as, -S(O)-), sulfonyl (such as, -S(O)-), 2 -), optionally substituted amino (such as, -NR ua -) or optionally substituted alkylene (such as, optionally substituted C 1-6 U 2 is O or S; n1 and n2 are each independently 0, 1, 2, or 3 (such as, wherein at least one of n1 and n2 is not 0); R ua are each independently hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C1-6 an alkoxy group) or an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl group); and R uc are each independently hydrogen (H), a hydroxyl group, an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), an optionally substituted haloalkyl group (such as an optionally substituted C 1-6 haloalkyl group), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group), an optionally substituted haloalkoxy group (such as an optionally substituted C 1-6 haloalkoxy group), an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl group), an optionally substituted halocycloalkyl group (such as an optionally substituted C 3-8 halocycloalkyl group), an amino group (such as -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached, and

[0374] D comprises an optionally substituted heterocyclic group (such as an optionally substituted 5- to 10-membered heterocyclic group, for example an optionally substituted bicyclic 5- to 10-membered heterocyclic group) (such as where the optional substituents include halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0375] Embodiment 2. The compound of Embodiment 1, wherein R 1 , R 2 and R 3 are each independently hydrogen (H) or an optionally substituted alkyl group.

[0376] Embodiment 3. The compound of Embodiment 1 or 2, wherein X and Y are each N, Y and Z are each N, or Y and Q are each N.

[0377] Embodiment 4. The compound of any one of Embodiments 1-3, wherein X is N, and wherein the first double bond is between Q and the adjacent carbon atom and the second double bond is between Y and Z.

[0378] Enumerated Embodiment 5. A compound according to any one of Enumerated Embodiments 1-3, wherein Z is N, and wherein the first double bond is between Q and the adjacent carbon atom and the second double bond is between X and Y.

[0379] Enumerated Embodiment 6. A compound according to any one of Enumerated Embodiments 1-3, wherein Q is N, and wherein the first double bond is between X and the adjacent carbon atom and the second double bond is between Y and Z.

[0380] Enumerated Embodiment 7. A compound according to any one of Enumerated Embodiments 1-6, wherein L 1 is a carbonyl (such as, -C(O)-), an alkylene (such as, optionally substituted C 1-6 alkylene), a sulfinyl (such as, -S(O)-) or a sulfonyl (such as, -S(O) 2 -).

[0381] Enumerated Embodiment 8. A compound according to any one of Enumerated Embodiments 1-7, wherein L 2 is and wherein:

[0382] n4 is 1, 2, or 3, and the dashed line represents an optional double bond (such as, wherein two double bonds are not attached to the same atom); and

[0383] R La and R Lb (if present) are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), and optionally wherein R La and R Lb together with the nitrogen atom to which they are attached each form an optionally substituted heterocyclic group.

[0384] Enumerated Embodiment 9. A compound according to any one of Enumerated Embodiments 1-8, wherein A comprises an optionally substituted C 6-10 aryl, and wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, or C 3-8 halocycloalkyl.

[0385] Enumerated Embodiment 10. A compound according to any one of Enumerated Embodiments 1-9, wherein A comprises wherein R 5 、R 6 and R 7 are each independently hydrogen (H), a halogen, an optionally substituted alkyl (such as an optionally substituted C 1-6 alkyl), an optionally substituted haloalkyl (such as an optionally substituted C 1-6 haloalkyl), an optionally substituted alkoxy (such as an optionally substituted C 1-6 alkoxy), an optionally substituted haloalkoxy (such as an optionally substituted C 1-6 haloalkoxy), an optionally substituted cycloalkyl (such as an optionally substituted C 3-8 cycloalkyl) or an optionally substituted halocycloalkyl (such as an optionally substituted C 3-8 halocycloalkyl) (such as wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0386] Example 11. The compound of Example 10, wherein A comprises

[0387] Example 12. The compound of any one of Examples 1-11, wherein B comprises and

[0388] wherein:

[0389] W 1 、W 3 and W 4 are each independently C or N;

[0390] W 2 is CR wa 、NR wa 、N、O, or S, and the dashed line represents an optional double bond (such as wherein two double bonds are not attached to the same atom);

[0391] W 5 、W 6 and W 7 are each independently CR wa or N (such as wherein b1, b2 and b3 are attached to L 1 、C and V 1 ) in any order or position; and

[0392] R wa (if present) is each independently hydrogen (H), halogen, or optionally substituted alkyl (such as optionally substituted C 1-6 alkyl) (such as wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these). Enumerated embodiment 13. The compound of enumerated embodiment 12, wherein B comprises

[0393] Enumerated embodiment 14. The compound of any one of enumerated embodiments 1-13, wherein B comprises and

[0394] wherein:

[0395] W 1 、W 3 and W 4 are each independently C or N;

[0396] W 2 is CR wa 、NR wa 、N, O, or S, and the dashed line represents an optional double bond (such as wherein two double bonds are not attached to the same atom);

[0397] W 5 、W 6 and W 7 are each independently CR wa or N (such as wherein b1 and b2 are attached to L 1 and C in any order or position);

[0398] R wa (if present) is each independently hydrogen (H), halogen, or optionally substituted alkyl (such as optionally substituted C 1-6 alkyl) (such as wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); and

[0399] V 1 comprises an optionally substituted heterocyclic group (such as, an optionally substituted heteroaryl).

[0400] Enumerated embodiment 15. The compound of enumerated embodiment 14, wherein B comprises

[0401] Enumerated embodiment 16. The compound of enumerated embodiment 14 or 15, wherein V 1 comprises and

[0402] wherein:

[0403] V a is N or CR vc ;

[0404] V b is NR Vc 、O or S;

[0405] R va and R vc (if present) are each independently hydrogen (H), halogen, or an optionally substituted alkyl group (such as, an optionally substituted C 1-6 alkyl group) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these), and wherein one or more R va may be present on V 1 .

[0406] Enumerated embodiment 17. The compound of enumerated embodiment 14 or 15, wherein V 1 comprises and wherein:

[0407] V a is N or CR vc ,

[0408] R va 、R vb 、and R vc (if present) are each independently hydrogen (H), halogen, or an optionally substituted alkyl group (such as, an optionally substituted C 1-6 alkyl group) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or a combination of any of these).

[0409] Embodiment 18. A compound according to any one of Embodiments 1 - 17, wherein C comprises or a stereoisomer thereof.

[0410] Embodiment 19. A compound according to any one of Embodiments 1 - 18, wherein C comprises or a stereoisomer thereof.

[0411] Embodiment 20. A compound according to any one of Embodiments 1 - 19, wherein U 1 is an optionally substituted C 1-6 alkylene (such as, -CR Ua R Ub - or -[CR Ua R Ub n3 -, where n3 is 1, 2, or 3, and where R ua and R ub (if present) are each independently hydrogen (H), an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl) or an optionally substituted alkoxy (such as, an optionally substituted C 1-6 alkoxy)).

[0412] Embodiment 21. A compound according to any one of Embodiments 1 - 20, wherein C comprises

[0413] Embodiment 22. A compound according to any one of Embodiments 1 - 21, wherein D comprises and wherein:

[0414] R da 、R bd 、R dc and R dd are each independently hydrogen (H), halogen, hydroxy, an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl) or an optionally substituted alkoxy (such as, an optionally substituted C 1-6 alkoxy); and

[0415] R 4 is hydrogen (H), an optionally substituted alkyl (such as, an optionally substituted C 1-6 ​(alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) (such as, wherein the optional substituents include halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0416] Embodiment 23. The compound of Embodiment 22, wherein D comprises Embodiment 24. The compound of Embodiment 22, wherein D comprises

[0417] Embodiment 25. The compound of Embodiment 1, wherein the compound comprises the structure of formula (IIa):

[0418]

[0419] or a pharmaceutically acceptable salt thereof, its stereoisomers, its analogs (such as, its deuterated analogs) or its solvates, wherein:

[0420] R 1 、R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy);

[0421] R 4 is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl);

[0422] R 5 、R 6 and R 7 are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C1-6 (haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) or optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl) (such as, where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these);

[0423] L 1 and L 2 are each independently a linking group;

[0424] X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as, where two double bonds are not attached to the same atom, and optionally where a double bond is present between Q and an adjacent carbon atom and / or between Y and Z);

[0425] W 1 , W 3 and W 4 are each independently C or N;

[0426] W 2 is CR wa , NR wa , N, O, or S, and the dashed line represents an optional double bond (such as, where two double bonds are not attached to the same atom);

[0427] W 5 , W 6 and W 7 are each independently CR wa or N;

[0428] R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8Naphthenyl, C 3-8 halogenated naphthenyl, or a combination of any of these);

[0429] U 1 is an oxy group (such as, -O-), a thio group (such as, -S-), a sulfinyl group (such as, -S(O)-), a sulfonyl group (such as, -S(O) 2 -), an optionally substituted amino group (such as, -NR ua -), or an optionally substituted alkylene group (such as, optionally substituted C 1-6 alkylene);

[0430] U 2 is O or S;

[0431] R ua each independently is hydrogen (H), an optionally substituted alkyl group (such as, optionally substituted C 1-6 alkyl), an optionally substituted alkoxy group (such as, optionally substituted C 1-6 alkoxy), or an optionally substituted naphthenyl group (such as, optionally substituted C 3-8 naphthenyl);

[0432] R uc each independently is hydrogen (H), a hydroxyl group, an optionally substituted alkyl group (such as, optionally substituted C 1-6 alkyl), an optionally substituted halogenated alkyl group (such as, optionally substituted C 1-6 halogenated alkyl), an optionally substituted alkoxy group (such as, optionally substituted C 1-6 alkoxy), an optionally substituted halogenated alkoxy group (such as, optionally substituted C 1-6 halogenated alkoxy), an optionally substituted naphthenyl group (such as, optionally substituted C 3-8 naphthenyl), an optionally substituted halogenated naphthenyl group (such as, optionally substituted C 3-8 halogenated naphthenyl), an amino group (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached;

[0433] n1 and n2 each independently are 0, 1, 2, or 3 (such as, where at least one of n1 and n2 is not 0); and

[0434] V 1 comprises an optionally substituted heterocyclic group (such as, optionally substituted heteroaryl).

[0435] Enumerated Embodiment 26. A compound of Enumerated Embodiment 1, wherein the compound comprises a structure of formula (IIb):

[0436]

[0437] or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as a deuterated analogue thereof), or a solvate thereof, wherein:

[0438] R 1 、R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as optionally substituted C 1-6 alkoxy);

[0439] R 4 is hydrogen (H), optionally substituted alkyl (such as optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as optionally substituted C 3-8 cycloalkyl);

[0440] R 5 、R 6 and R 7 are each independently hydrogen (H), halogen, optionally substituted alkyl (such as optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as optionally substituted C 3-8 cycloalkyl) or optionally substituted halocycloalkyl (such as optionally substituted C 3-8 halocycloalkyl) (such as wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of any of these);

[0441] R La and RLb (if present) each independently is hydrogen (H), an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl) or an optionally substituted alkoxy (such as, an optionally substituted C 1-6 alkoxy), and optionally wherein R La and R Lb each together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group;

[0442] X, Y, Z, and Q each independently is C or N, and the dashed line represents an optional double bond (such as, wherein two double bonds are not attached to the same atom, and optionally wherein a double bond is present between Q and an adjacent carbon atom and / or between Y and Z);

[0443] W 1 、W 3 and W 4 each independently is C or N;

[0444] W 2 is CR wa 、NR wa 、N, O, or S, and the dashed line represents an optional double bond (such as, wherein two double bonds are not attached to the same atom);

[0445] W 5 、W 6 and W 7 each independently is CR wa or N;

[0446] R wa (if present) each independently is hydrogen (H), a halogen, or an optionally substituted alkyl (such as, an optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: a halogen, a C 1-6 alkyl, a C 1-6 haloalkyl, a C 1-6 alkoxy, a C 1-6 haloalkoxy, a C 3-8 cycloalkyl, a C 3-8 halocycloalkyl, or any combination of these);

[0447] U 1 is an oxy group (such as, -O-), a thio group (such as, -S-), a sulfinyl group (such as, -S(O)-), a sulfonyl group (such as, -S(O) 2 -), an optionally substituted amino group (such as, -NR ua -), or an optionally substituted alkylene group (such as, an optionally substituted C 1-6 alkylene);

[0448] U 2 is O or S;

[0449] R ua each independently is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl);

[0450] R uc each independently is hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached;

[0451] n1 and n2 each independently are 0, 1, 2, or 3 (such as, where at least one of n1 and n2 is not 0); and

[0452] V 1 comprises an optionally substituted heterocyclic group (such as, optionally substituted heteroaryl).

[0453] Compound of Embodiment 27. The compound of Embodiment 1, wherein the compound comprises a structure of formula (IIc):

[0454]

[0455] or a pharmaceutically acceptable salt thereof, its stereoisomers, its analogs (such as, its deuterated analogs) or its solvates, wherein:

[0456] R 1 、R 2 and R 3Each is independently hydrogen (H), a halogen, a hydroxyl group, an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group) or an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group);

[0457] R 4 is hydrogen (H), an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group) or an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl group);

[0458] R 5 , R 6 and R 7 are each independently hydrogen (H), a halogen, an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), an optionally substituted haloalkyl group (such as an optionally substituted C 1-6 haloalkyl group), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group), an optionally substituted haloalkoxy group (such as an optionally substituted C 1-6 haloalkoxy group), an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl group) or an optionally substituted halocycloalkyl group (such as an optionally substituted C 3-8 halocycloalkyl group) (such as, where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these);

[0459] X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as, where two double bonds are not attached to the same atom, and optionally where a double bond is present between Q and an adjacent carbon atom and / or between Y and Z);

[0460] W 1 , W 3 and W 4 are each independently C or N;

[0461] W 2 is CR wa , NR wa, N, O, or S, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom);

[0462] W 5 , W 6 and W 7 are each independently CR wa or N;

[0463] R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as optionally substituted C 1-6 alkyl) (such as where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these);

[0464] U 1 is oxy (such as, -O-), thio (such as, -S-), sulfinyl (such as, -S(O)-), sulfonyl (such as, -S(O) 2 -), optionally substituted amino (such as, -NR ua -), or optionally substituted alkylene (such as optionally substituted C 1-6 alkylene);

[0465] U 2 is O or S;

[0466] R ua are each independently hydrogen (H), optionally substituted alkyl (such as optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as optionally substituted C 1-6 alkoxy);

[0467] R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as optionally substituted C 3-8cycloalkyl), optionally substituted haloalkyl (such as, optionally substituted C 3-8 haloalkyl), amino (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached;

[0468] n1 and n2 are each independently 0, 1, 2, or 3 (such as, where at least one of n1 and n2 is not 0); and

[0469] V 1 comprises an optionally substituted heterocyclic group (such as, optionally substituted heteroaryl).

[0470] Enumerated embodiment 28. A compound according to any one of enumerated embodiments 1-27, wherein X is N; X and Y are N; Y and Z are N; or Y and W are N.

[0471] Enumerated embodiment 29. A compound according to any one of enumerated embodiments 25-28, wherein W 1 , W 2 , W 3 , W 4 , W 5 , W 6 or W 7 is at least one of N or NR wa ; and wherein R wa is hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, where the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 haloalkyl, or any combination of these).

[0472] Enumerated embodiment 30. A compound according to any one of enumerated embodiments 1-29, wherein R 1 is optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl).

[0473] Enumerated embodiment 31. A compound according to any one of enumerated embodiments 1-30, wherein at least one of R 1 , R 2 and R 3 is not H.

[0474] Enumerated Embodiment 32. A compound of any one of Enumerated Embodiments 1 - 31, wherein R 4 is C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 alkyl substituted with one or more C 1-6 cycloalkyl, or C 3-8 alkyl substituted with one or more C 1-6 halocycloalkyl.

[0475] Enumerated Embodiment 33. A compound of any one of Enumerated Embodiments 1 - 32, wherein R 5 , R 6 and R 7 are each independently halogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 3-8 alkyl substituted with one or more C 1-6 cycloalkyl, or C 3-8 alkyl substituted with one or more C 1-6 halocycloalkyl.

[0476] Enumerated Embodiment 34. A compound of any one of Enumerated Embodiments 1 - 33, wherein R 6 is halogen (such as, fluorine or chlorine).

[0477] Enumerated Embodiment 35. A compound of any one of Enumerated Embodiments 1 - 34, wherein R 5 and R 7 are each independently halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0478] Enumerated Embodiment 36. A compound of any one of Enumerated Embodiments 1 - 35, wherein R 5 , R6 and R 7 at least one of which is not H.

[0479] Example 37. A compound according to any one of Examples 1-36, wherein U 1 is O or methylene (CH 2 ). Example 38. A compound according to any one of Examples 1-37, wherein n1 is 1 and / or wherein n2 is 1.

[0480] Example 39. A compound according to any one of Examples 1-38, wherein U 2 is O and / or wherein R ua is H or C 1-6 alkyl.

[0481] Example 40. A compound according to any one of Examples 1-39, wherein V 1 comprises and wherein:

[0482] V a is N or CR vc ,

[0483] R va , R vb and R vc (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of any of these).

[0484] Example 41. The compound of Example 1, wherein the compound comprises the structure of formula (IIIa):

[0485]

[0486] or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as, a deuterated analogue thereof) or a solvate thereof, wherein:

[0487] U 1is an oxy group (such as, -O-), a thio group (such as, -S-), a sulfinyl group (such as, -S(O)-), a sulfonyl group (such as, -S(O) 2 -), an optionally substituted amino group (such as, -NR ua -), or an optionally substituted alkylene group (such as, an optionally substituted C 1-6 alkylene group);

[0488] R uc each independently is hydrogen (H), a hydroxyl group, an optionally substituted alkyl group (such as, an optionally substituted C 1-6 alkyl group), an optionally substituted haloalkyl group (such as, an optionally substituted C 1-6 haloalkyl group), an optionally substituted alkoxy group (such as, an optionally substituted C 1-6 alkoxy group), an optionally substituted haloalkoxy group (such as, an optionally substituted C 1-6 haloalkoxy group), an optionally substituted cycloalkyl group (such as, an optionally substituted C 3-8 cycloalkyl group), an optionally substituted halocycloalkyl group (such as, an optionally substituted C 3-8 halocycloalkyl group), an amino group (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached;

[0489] n1 is 0, 1, 2, or 3; and

[0490] V 1 is an optionally substituted heterocyclic group.

[0491] The compound of Enumerated Embodiment 42. The compound of Enumerated Embodiment 41, wherein V 1 comprises and wherein:

[0492] V a is N or CR vc ,

[0493] R va and R vc (if present) each independently is hydrogen (H), a halogen, or an optionally substituted alkyl group (such as, an optionally substituted C 1-6 alkyl group) (such as, wherein the optional substituents include one or more of the following: a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 3-8 cycloalkyl group, or any combination of these), and wherein one or more Rva may be present in V 1 above.

[0494] Embodiment 43. The compound of Embodiment 41, wherein V 1 comprises and wherein:

[0495] V a is N or CR vc ,

[0496] R va , R vb and R vc (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

[0497] Embodiment 44. The compound of Embodiment 1, wherein the compound comprises the structure of formula (IIIb):

[0498]

[0499] or a pharmaceutically acceptable salt thereof, its stereoisomers, its analogs (such as, its deuterated analogs) or its solvates, wherein:

[0500] R 4 is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl);

[0501] R 5 , R 6 and R 7 are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) or optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); and

[0502] R uc each independently is hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or an isotope, where one or more R uc are present on the ring to which they are attached.

[0503] The compound of embodiment 44, wherein R 4 is C 1-6 alkyl (such as, methyl), deuterated C 1-6 alkyl (such as, deuterated methyl, e.g., CD 3 ), C 3-8 cycloalkyl (such as, cyclopropyl, e.g., ), C 3-8 alkyl substituted with one or more C 1-6 cycloalkyl (such as, cyclopropylalkyl, including cyclopropylmethyl, such as ), C 3-8 halocycloalkyl (such as, 1-halocyclopropyl, including 1-fluorocyclopropyl, such as ) or C substituted with one or more C3-8 Halocycloalkyl-substituted C 1-6 alkyl (such as, 1-halocyclopropylalkyl, including 1-fluorocyclopropylmethyl, such as ).

[0504] Compound of embodiment 46 listed. Compound of embodiment 44 or 45 listed, wherein R 5 , R 6 and R 7 are each independently halogen (such as, fluorine or chlorine), C 1-6 alkyl (such as, methyl), C 3-8 cycloalkyl (such as, cyclopropyl, for example C 3-8 cycloalkyl (such as, cyclopropyl), C substituted with one or more C 3-8 cycloalkyl 1-6 alkyl (such as, cyclopropylalkyl, including cyclopropylmethyl), C 3-8 halocycloalkyl (such as, 1-halocyclopropyl, including 1-fluorocyclopropyl) or C substituted with one or more C 3-8 halocycloalkyl 1-6 alkyl (such as, 1-halocyclopropylalkyl, including 1-fluorocyclopropylmethyl).

[0505] Compound of embodiment 47 listed. Compound of embodiment 1 listed, wherein the compound comprises a structure of formula (IIIc):

[0506]

[0507] or a pharmaceutically acceptable salt thereof, its stereoisomers, its analogs (such as, its deuterated analogs) or its solvates, wherein:

[0508] X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as, wherein two double bonds are not connected to the same atom, and optionally wherein a double bond is present between Q and an adjacent carbon atom and / or between Y and Z);

[0509] W 1 , W 3 and W 4 are each independently C or N;

[0510] W 2 is CR wa , NR wa , N, O, or S, and the dashed line represents an optional double bond (such as, wherein two double bonds are not connected to the same atom);

[0511] W 5 , W 6 and W 7 are each independently CRwa or N;

[0512] R wa (if present) each independently is hydrogen (H), a halogen, or an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group) (such as, where the optional substituents include one or more of the following: a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a C 3-8 cycloalkyl group, a C 3-8 halocycloalkyl group, or any combination of these); and

[0513] R uc each independently is hydrogen (H), a hydroxyl group, an optionally substituted alkyl group (such as an optionally substituted C 1-6 alkyl group), an optionally substituted haloalkyl group (such as an optionally substituted C 1-6 haloalkyl group), an optionally substituted alkoxy group (such as an optionally substituted C 1-6 alkoxy group), an optionally substituted haloalkoxy group (such as an optionally substituted C 1-6 haloalkoxy group), an optionally substituted cycloalkyl group (such as an optionally substituted C 3-8 cycloalkyl group), an optionally substituted halocycloalkyl group (such as an optionally substituted C 3-8 halocycloalkyl group), an amino group (such as -NR N1 R N2 , as described herein) or an isotope, where one or more R uc may be present on the ring to which they are attached.

[0514] The compound of embodiment 48. The compound of embodiment 47, wherein is

[0515] The compound of embodiment 49. The compound of embodiment 47 or 48, wherein is

[0516]

[0517] The compound of embodiment 50. A compound according to Table 1 or a pharmaceutically acceptable salt thereof, its stereoisomers, its analogs (such as its deuterated analogs) or its solvates.

[0518] Enumerated Embodiment 51. A pharmaceutical composition comprising a compound of any one of Enumerated Embodiments 1-50 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as a deuterated analogue thereof), or a solvate thereof, and at least one pharmaceutically acceptable excipient.

[0519] Enumerated Embodiment 52. A method for treating or prophylactically treating a GLP-1 related disease, disorder or condition, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of Enumerated Embodiments 1-50 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as a deuterated analogue thereof), or a solvate thereof, or the pharmaceutical composition of Enumerated Embodiment 51.

[0520] Enumerated Embodiment 53. The method of Enumerated Embodiment 52, wherein the disease, disorder or condition is selected from the group consisting of: type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (Type 1b), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY) in young people, latent autoimmune diabetes in adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), overweight, weight gain caused by other drugs, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, hyperlipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, arteriosclerosis, coronary heart disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, cerebral infarction, peripheral vascular disease, endothelial dysfunction, vascular compliance damage, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue diseases, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, dementia, schizophrenia, polycystic ovary syndrome (PCOS) or any combination thereof.

[0521] Enumerated Embodiment 54. A method for treating or prophylactically treating diabetes in an individual in need thereof, the method comprising administering to the individual in need thereof an effective amount of a compound of any one of Enumerated Embodiments 1-50 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as a deuterated analogue thereof) or a solvate thereof, or a pharmaceutical composition of Enumerated Embodiment 51.

[0522] Enumerated Embodiment 55. A method for treating or prophylactically treating type 2 diabetes in an individual in need thereof, the method comprising administering to the individual in need thereof an effective amount of a compound of any one of Enumerated Embodiments 1-50 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as a deuterated analogue thereof), or a solvate thereof, or a pharmaceutical composition of Enumerated Embodiment 51.

[0523] Enumerated Embodiment 56. A method for treating or prophylactically treating obesity or overweight in an individual in need thereof, the method comprising administering to the individual in need thereof an effective amount of a compound of any one of Enumerated Embodiments 1-50 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as a deuterated analogue thereof), or a solvate thereof, or a pharmaceutical composition of Enumerated Embodiment 51.

[0524] Enumerated Embodiment 57. A method for regulating insulin levels in an individual in need of such regulation, the method comprising administering to the individual in need thereof an effective amount of a compound of any one of Enumerated Embodiments 1-50 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as a deuterated analogue thereof), or a solvate thereof, or a pharmaceutical composition of Enumerated Embodiment 51.

[0525] Enumerated Embodiment 58. A method for regulating glucose levels in an individual in need of such regulation, the method comprising administering to the individual in need thereof an effective amount of a compound of any one of Enumerated Embodiments 1-50 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as a deuterated analogue thereof), or a solvate thereof, or a pharmaceutical composition of Enumerated Embodiment 51.

[0526] Enumerated Embodiment 59. The method of any one of Enumerated Embodiments 52-58, the method further comprising administering to the individual an additional therapy or therapeutic agent.

[0527] Enumerated Embodiment 60. The method of Enumerated Embodiment 59, wherein the additional therapy or therapeutic agent is selected from the group consisting of: an anti-diabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an anti-emetic agent, an active agent for treating non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, diet monitoring, physical activity, or a combination thereof.

[0528] Enumerated Embodiment 61. A compound of any one of Enumerated Embodiments 1-50 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as a deuterated analogue thereof), or a solvate thereof, for use in treating or prophylactically treating a GLP-1 related disease, disorder or condition.

[0529] Use of a compound according to any one of the recited embodiments 1 - 50 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analogue thereof (such as a deuterated analogue thereof), or a solvate thereof in the preparation of a medicament for the treatment or prophylactic treatment of GLP-1 related diseases, disorders or conditions.

[0530] Recited embodiment 63. The compound for use in said use according to recited embodiment 61 or the use according to recited embodiment 62, wherein the disease, disorder or condition is selected from the group consisting of: type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (Type 1b), young-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY) in young people, latent autoimmune diabetes in adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), overweight, weight gain caused by other drugs, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, hyperlipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular diseases, arteriosclerosis, coronary heart disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, cerebral infarction, peripheral vascular disease, endothelial dysfunction, vascular compliance impairment, restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue diseases, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, dementia, schizophrenia, polycystic ovary syndrome (PCOS) or any combination thereof. Examples

[0531] Abbreviations (as used herein):

[0532]

[0533]

[0534] In the following examples, when the structural formula of a compound does not conform to its chemical name, the structural formula of the compound shall prevail.

[0535] Example 1: (S)-1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (Intermediate I-1)

[0536]

[0537] Scheme 1 shows non-limiting steps A to J for preparing Intermediate I-1.

[0538] Scheme 1

[0539]

[0540] Step A: N-(2,2-Dimethoxyethyl)-1H-imidazole-1-carboxamide (1-3)

[0541]

[0542] At -10 °C, Compound 1-2 (22.69 g, 215.85 mmol) was added to a mixture of Compound 1-1 (50.00 g, 308.36 mmol) in ethyl acetate (125 mL). After the addition was complete, the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was cooled to 0 °C and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (40 - 44% ethyl acetate / petroleum ether) to obtain Compound 1-3 (42.00 g, 79%) as a white solid.

[0543] LC-MS: ESI-MS (m / z): [M+H] + = 200.1.

[0544] Step B: Di-tert-butyl 1-(4-fluoro-3,5-dimethylphenyl)hydrazine-1,2-dicarboxylate (1-5)

[0545]

[0546] At -70 °C, n-butyllithium (85.1 mL, 2.5 M in hexane, 212.76 mmol) was added dropwise to a mixture of Compound 1-4 (45.00 g, 221.62 mmol) in tetrahydrofuran (450 mL), and the mixture was stirred for 1 h. Then, di-tert-butyl azodicarboxylate (45.93 g, 199.46 mmol) was added dropwise at -40 °C, and the mixture was stirred for 0.5 h. The reaction mixture was warmed to 25 °C over 1 h and quenched with saturated ammonium chloride solution (460 mL). The reaction mixture was extracted with heptane (230 mL). The organic layer was separated and concentrated. Heptane (70 mL) was added, and the mixture was heated to 70 °C to facilitate dissolution. The solution was cooled to 25 °C, and a white solid precipitated over 1 h. The precipitate was collected by filtration, washed with heptane (23 mL) and dried to give Compound 1-5 (42.00 g, 53%) as a white solid.

[0547] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.56 (s, 1H), 7.07–6.96 (m, 2H), 2.19 (s, 6H), 1.50–1.37 (m, 18H).

[0548] Step C: (S)-3-aminobutyronitrile hydrochloride (1-7)

[0549]

[0550] At 25 °C, HCl (4 M in 1,4-dioxane, 50 mL) was added to a mixture of Compound 1-6 (27 g, 146.55 mmol) in dichloromethane (150 mL), and the mixture was stirred for 3 h. The reaction solution was concentrated to give crude Compound 1-7 (28.0 g) as a colorless oil.

[0551] Step D: Ethyl (S)-3-((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)propanoate (1-8)

[0552]

[0553] At 25 °C, triethylamine (29.66 g, 293.1 mmol) and ethyl acrylate (17.61 g, 175.86 mmol) were added to a mixture of compound 1-7 (17.67 g, 146.55 mmol) in ethanol (85 mL). The reaction mixture was stirred at 70 °C for 3 h and then cooled to 25 °C. Di-tert-butyl dicarbonate (38.38 g, 175.86 mmol) was added, and the reaction mixture was stirred at 25 °C for 14 h. N-Methylpiperazine (3 mL, 27.06 mmol) was added, and the mixture was stirred for 4 h. Dilute HCl solution (50 mL, 1 M) was added, and the mixture was extracted with toluene (50 mL × 3). The organic layer was separated, washed with an aqueous solution of sodium chloride (50 mL, 15 wt%), and concentrated to dryness under reduced pressure to obtain crude compound 1-8 (41.67 g) as a brown oil.

[0554] ESI-MS (m / z): [M+H] + = 284.9.

[0555] Step E: tert-Butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (1-9)

[0556]

[0557] At 25 °C, potassium tert-butoxide (16.44 g, 146.54 mmol) was added to a mixture of crude compound 1-8 (41.67 g) in tetrahydrofuran (410 mL), and the mixture was stirred for 1 h. Dilute HCl (1.2 L, 2 M) was added, and the internal temperature was maintained at 15 °C. The reaction mixture was extracted with ethyl acetate (200 mL × 3). The organic layer was separated and washed with an aqueous solution of sodium chloride (300 mL × 2, 15 wt%) to obtain crude compound 1-9 (36.00 g) as a brown oil.

[0558] ESI-MS (m / z): [M+H] + = 238.9.

[0559] 1 H NMR (400 MHz, DMSO-d 6 ): δ 4.58–4.42 (m, 1H), 4.01–3.88 (m, 1H), 2.96 (s, 1H), 2.50 (s, 1H), 2.38–2.26 (m, 1H), 2.19 (dd, J = 17.6, 3.4 Hz, 1H), 1.41 (s, 9H), 1.21 (d, J = 6.6 Hz, 3H).

[0560] Step F: tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1-10)

[0561]

[0562] To a mixture of compound 1-5 (42.00 g, 118.50 mmol) in N-methyl-2-pyrrolidone (126 mL) was added methanesulfonic acid (22.78 g, 237 mmol), and the mixture was stirred at 80 °C for 7 h. The reaction mixture was cooled to 25 °C and toluene (252 mL), potassium carbonate (18.02 g, 130.35 mmol), and water (252 mL) were added. The reaction mixture was stirred at 25 °C for 10 minutes (min). The organic layer was separated, and to it was added a solution of compound 1-9 (27.82 g, 116.74 mmol) in toluene (126 mL), pyridine hydrochloride (1.35 g, 11.67 mmol), and toluene (84 mL). The reaction mixture was stirred at 90 °C for 1 h and cooled to 25 °C. The reaction mixture was washed with aqueous sodium hydroxide solution (252 mL, 1 M). The organic layer was separated and concentrated to dryness under reduced pressure to give compound 1-10 (34.80 g, 80%) as a brown oil.

[0563] ESI-MS (m / z): [M+H] + = 374.9.

[0564] 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.22 (d, J = 6.4 Hz, 2H), 5.18 (s, 2H), 5.07 (d, J = 43.4 Hz, 1H), 4.24–4.02 (m, 1H), 3.14–2.90 (m, 1H), 2.48–2.38 (m, 2H), 2.25 (d, J = 1.2 Hz, 6H), 1.43 (s, 9H), 1.24 (d, J = 6.0 Hz, 3H).

[0565] Step G: tert-Butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1-11)

[0566]

[0567] To a mixture of Compound 1-10 (11.00 g, 29.38 mmol) and Compound 1-3 (17.56 g, 88.14 mmol) in N,N-dimethylacetamide (110 mL) was added potassium tert-butoxide (19.78 g, 176.28 mmol), and the mixture was stirred at 25 °C for 2 h. At 0 °C, the reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with saturated sodium chloride (50 mL × 3), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0 - 5% MeOH / dichloromethane) to give Compound 1-11 (14.00 g, 94%) as a yellow solid.

[0568] ESI-MS (m / z): [M+H] + = 505.9.

[0569] Step H: tert-Butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1-12)

[0570]

[0571] To a mixture of Compound 1-11 (14.00 g, 27.69 mmol) in tetrahydrofuran (140 mL) was added methanesulfonic acid (2.66 g, 27.69 mmol), and the mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to 25 °C, and a solution of potassium phosphate (2.35 g, 11.08 mmol) in water (56 mL) and di-tert-butyl dicarbonate (4.83 g, 22.15 mmol) were added. The resulting mixture was stirred at 25 °C for 1 h, diluted with water (150 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated sodium chloride (50 mL × 3), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Then, the residue was purified by silica gel column chromatography (20 - 30% EA / PE) to give Compound 1-12 (8.00 g, 65%) as a yellow solid.

[0572] ESI-MS (m / z): [M+H] + = 442.2.

[0573] Step I: tert-Butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1-14)

[0574]

[0575] To a mixture of Compound 1-12 (1.00 g, 2.27 mmol) and Compound 1-13 (778 mg, 3.40 mmol) in N-methyl-2-pyrrolidone (10 mL) were added copper(I) iodide (216 mg, 1.14 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (323 mg, 2.27 mmol), and potassium carbonate (941 mg, 6.81 mmol). The mixture was stirred at 120 °C for 16 h under a nitrogen atmosphere. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (50 - 62%, ethyl acetate / petroleum ether) to give Compound 1-14 (1.10 g, 82%) as a yellow solid.

[0576] ESI-MS (m / z): [M+H] + = 590.0.

[0577] Step J: (S)-1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (I-1)

[0578]

[0579] To a mixture of Compound 1-14 (450 mg) in dichloromethane (4.5 mL) was added HCl (4 M in 1,4-dioxane, 1.9 mL), and the mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was redissolved in ethyl acetate and washed with saturated NaHCO 3 solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give Compound I-1 (350 mg, 94%) as a yellow solid.

[0580] ESI-MS (m / z): [M+H] + = 489.9.

[0581] Example 2: (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (Intermediate I-2)

[0582]

[0583] Scheme 2 shows the non-limiting Steps A to E for preparing Intermediate I-2.

[0584] Scheme 2

[0585]

[0586] Step A: Ethyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (2-3)

[0587]

[0588] Under a nitrogen atmosphere, trimethylchlorosilane (1.65 g, 15.2 mmol) and 1,2-dibromoethane (2.86 g, 15.2 mmol) were added to a suspension of zinc powder (9.00 g, 138.5 mmol) in N,N-dimethylformamide (28 mL). The reaction mixture was stirred at 25 °C for 5 min. A solution of Compound 2-2 (25.00 g, 104.1 mmol) in N,N-dimethylformamide (42 mL) was added and the mixture was stirred at 25 °C for 20 min. Palladium acetate (780 mg, 3.5 mmol), (4-N,N-dimethylamino)phenylbis-tert-butyl (1.84 g, 6.93 mmol) and Compound 2-1 (9.31 g, 34.7 mmol) were added, and the mixture was heated to 55 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to 25 °C, quenched with diluted HCl (4 M), diluted with water (100 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0-15%, ethyl acetate / petroleum ether) to give Compound 2-3 (9.12 g, 87%) as a white solid.

[0589] ESI-MS (m / z): [M+H] + = 302.1.

[0590] Step B: (S)-Ethyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (2-4)

[0591]

[0592] Compound 2-3 (16.67 g) was separated by SFC to obtain Compound 2-4 (8.24 g) and its enantiomer (7.28 g).

[0593] The separation conditions were as follows:

[0594] Apparatus: Kep300.

[0595] Column: Chiral ART Amylose KBN 5μm column.

[0596] Temperature: 25 °C.

[0597] Solvent: ethanol = 100 (V). Flow rate: 100 mL / min.

[0598] The analysis conditions were as follows:

[0599] Apparatus: Shimadzu LC 20CNZ, equipped with a UV detector or SPD M20A

[0600] Column: Chiral ART Amylose KBN (5μm), 0.46 cm I.D. × 25 cm L.

[0601] Column temperature: 25 °C

[0602] Solvent: ethanol = 100 (V)

[0603] Flow rate: 1.0 mL / min

[0604] Retention time of Compound 2-4: 15.980 min, retention time of the enantiomer: 9.534 min.

[0605] Step C: (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (2-5)

[0606]

[0607] To a mixture of Compound 2-4 (7.24 g, 24.0 mmol) in MeOH (109 mL) was added an aqueous sodium hydroxide solution (26.4 mL, 2 M, 52.8 mmol), and the reaction mixture was heated to 65 °C and stirred for 2 h. The reaction mixture was cooled to 0 °C and dilute HCl (23.1 mL, 2.4 M) and water (54 mL) were slowly added. The reaction mixture was stirred for another 1 h and filtered. The filter cake was dried to obtain Compound 2-5 (5.62 g, 86%), as a white solid.

[0608] ESI-MS (m / z): [M-H] - = 272.0

[0609] Step D: (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (2-6)

[0610]

[0611] Under a nitrogen atmosphere and at 0 °C, thionyl chloride (2.21 g, 18.6 mmol) was added dropwise to a mixture of compound 2-5 (4.23 g, 15.5 mmol) in N,N-dimethylacetamide (42 mL), and the reaction mixture was stirred for 1 h. N-Methylaniline (1.99 g, 18.7 mmol) and triethylamine (3.12 g, 30.9 mmol) were added, and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with water (28 mL) and filtered, and the filter cake was dried to obtain compound 2-6 (5.39 g, 96%) as a white solid.

[0612] ESI-MS (m / z): [M+H] + = 363.2

[0613] Step E: (S)-1-(Cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (I-2)

[0614]

[0615] Under a nitrogen atmosphere and at 0 °C, sodium hydride (0.33 g, 8.3 mmol) was added to a mixture of compound 2-6 (2.00 g, 5.5 mmol) in 1,3-dimethyl-2-imidazolidinone (30 mL) and stirred for 40 min. Chloro-acetonitrile (0.83 g, 11.0 mmol) was added dropwise. The reaction mixture was heated to 75 °C and stirred for 12 h. The reaction was cooled to 25 °C, quenched with water (50 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to obtain compound I-2 (2.12 g, 96%) as a white solid.

[0616] ESI-MS (m / z): [M+H] + = 402.2

[0617] Example 3: 3-(6-(5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-bicyclo[3.1.0]hex-6-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 23)

[0618]

[0619] Scheme 3 shows the non-limiting steps A to F for preparing Compound 23.

[0620] Scheme 3

[0621]

[0622] Step A: (3aR,6aS)-Tetrahydro-4H-cyclopenta[d][1,3,2]dioxathiolane 2-oxide (23-2)

[0623]

[0624] At 0 °C, thionyl chloride (1.75 g, 14.7 mmol) was added dropwise to a mixture of Compound 23-1 (1.00 g, 9.8 mmol) and triethylamine (3.96 g, 39.2 mmol) in dichloromethane (20 mL), and the mixture was stirred for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure to obtain crude Compound 23-2 (1.45 g) as a brown oil.

[0625] Step B: (3aR,6aS)-Tetrahydro-4H-cyclopenta[d][1,3,2]dioxathiolane 2,2-dioxide (23-3)

[0626]

[0627] At 0 °C, sodium periodate (2.51 g, 11.7 mmol) and ruthenium(III) chloride (40.6 mg, 0.2 mmol) were added to a mixture of compound 23-2 (1.45 g, 9.8 mmol) in acetonitrile (10 mL) and water (10 mL). The reaction mixture was stirred at 25 °C for 1 h and concentrated to dryness under reduced pressure. The residue was dissolved in dichloromethane (20 mL), washed with water (20 mL), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol / dichloromethane) to give compound 23-3 (800 mg, 50%) as a brown oil.

[0628] Step C: 1-(6-Cyanobicyclo[3.1.0]hex-6-yl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (23-4)

[0629]

[0630] Under a nitrogen atmosphere and at 0 °C, potassium bis(trimethylsilyl)amide (1.5 mL, 1 M in tetrahydrofuran, 1.5 mmol) was added dropwise to a mixture of intermediate I-2 (200.0 mg, 0.5 mmol) and compound 23-3 (245.7 mg, 1.5 mmol) in tetrahydrofuran (4 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to give compound 23-4 (168 mg, 72%) as a yellow oil.

[0631] ESI-MS (m / z): [M+H] + = 468.0.

[0632] Step D: 5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-(6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)bicyclo[3.1.0]hex-6-yl)-N-phenyl-1H-indole-2-carboxamide (23-5)

[0633]

[0634] A mixture of compound 23-4 (168 mg, 0.36 mmol), hydroxylamine hydrochloride (249.7 mg, 3.6 mmol) and sodium bicarbonate (301.8 mg, 3.6 mmol) in dimethyl sulfoxide (3 mL) was heated to 60 °C and stirred for 13 h. The reaction mixture was cooled to 25 °C, quenched with saturated sodium chloride (10 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in dimethyl sulfoxide (2.5 mL), then carbonyl diimidazole (93.9 mg, 0.58 mmol) and 1,8-diazabicycloundec-7-ene (110.0 mg, 0.72 mmol) were added. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated sodium chloride (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (0 - 30% ethyl acetate / petroleum ether) to give compound 23-5 (21 mg, 11%) as a brown solid.

[0635] ESI-MS (m / z): [M-H] - = 525.0.

[0636] Step E: 5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1-(6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)bicyclo[3.1.0]hex-6-yl)-1H-indole-2-carboxylic acid (23-6)

[0637]

[0638] To a mixture of compound 23-5 (21.0 mg, 0.04 mmol) in 2-methoxyethanol (1.5 mL) was added potassium hydroxide (30.0 mg, 0.53 mmol). The reaction mixture was heated to 100 °C and stirred for 7 h. The reaction mixture was cooled to 0 °C, and diluted HCl (6 M) (pH = 2) was added slowly. The reaction mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / dichloromethane) to give compound 23-6 (5 mg, 29%) as a brown solid.

[0639] ESI-MS (m / z): [M-H] - = 436.0.

[0640] Step F: 3-(6-(5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-bicyclo[3.1.0]hex-6-yl)-1,2,4-oxadiazol-5(4H)-one

[0641]

[0642] To a mixture of compound 23-13 (5.0 mg, 0.011 mmol) in N,N-dimethylformamide (1.5 mL) was added 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.9 mg, 0.017 mmol), intermediate I-1 (5.6 mg, 0.011 mmol), and N,N-diisopropylethylamine (7.4 mg, 0.057 mmol), and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / dichloromethane) to give compound 23 (4.0 mg, 39%) as a white solid.

[0643] ESI-MS (m / z): [M+H]+ = 909.7.

[0644] 1 H NMR (400 MHz, CDCl 3 ): δ 11.41 (s, 1H), 8.13 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.50 (s, 1H), 7.30 - 7.26 (m, 2H), 7.16 (d, J = 5.9 Hz, 2H), 6.66 (s, 1H), 6.61 (d, J = 1.5 Hz, 1H), 6.31 (d, J = 2.9 Hz, 1H), 5.79 (d, J = 6.6 Hz, 1H), 4.44 (dd, J = 13.4, 4.7 Hz, 1H), 4.12 (s, 3H), 3.92–3.78 (m, 2H), 3.62–3.51 (m, 1H), 3.17 - 2.94 (m, 3H), 2.29 (s, 6H), 2.06–1.96 (m, 1H), 1.84 - 1.52 (m, 12H), 1.34 (s, 3H), 1.28 (s, 3H), 1.26 (s, 3H).

[0645] Example 4: 3-(6-(5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-3-oxabicyclo[3.1.0]hex-6-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 29)

[0646]

[0647] Scheme 4 shows the non-limiting Steps A to E for preparing Compound 29.

[0648] Scheme 4

[0649]

[0650] Step A: (3aR,6aS)-Tetrahydrofuro[3,4-d][1,3,2]dioxathiolane 2,2-dioxide (29-2)

[0651]

[0652] At 0 °C, thionyl chloride (1.7 g, 14.41 mmol) was added dropwise to a mixture of Compound 29-1 (1.0 g, 9.61 mmol) and triethylamine (3.9 g, 38.42 mmol) in dichloromethane (20 mL) and stirred for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure. The residue was dissolved in methanol (8 mL) and water (2 mL) and sodium periodate (2.5 g, 11.59 mmol) and ruthenium(III) chloride (40.1 mg, 0.19 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 2 h and concentrated to dryness under reduced pressure. The residue was dissolved in dichloromethane (20 mL), washed with water (20 mL), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / petroleum ether) to give Compound 29-2 (1.1 g, 69%) as a white solid.

[0653] Step B: 1-(6-Cyano-3-oxabicyclo[3.1.0]hex-6-yl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (29-3)

[0654]

[0655] Under a nitrogen atmosphere and at 0 °C, potassium bis(trimethylsilyl)amide (1.5 mL, 1 M in tetrahydrofuran, 1.5 mmol) was added dropwise to a mixture of intermediate I-2 (211.5 mg, 0.53 mmol) and compound 29-2 (350.0 mg, 2.11 mmol) in tetrahydrofuran (4 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / petroleum ether) to give compound 29-3 (58 mg, 24%) as a yellow solid.

[0656] ESI-MS (m / z): [M+H] + = 470.7.

[0657] Step C: 5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-(6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-oxabicyclo[3.1.0]hex-6-yl)-N-phenyl-1H-indole-2-carboxamide (29-4)

[0658]

[0659] A mixture of compound 29-3 (58.0 mg, 0.12 mmol), hydroxylamine hydrochloride (85.6 mg, 1.24 mmol), and N,N-diisopropylethylamine (159.6 mg, 1.24 mmol) in dimethyl sulfoxide (2 mL) was heated to 60 °C and stirred for 24 h. The reaction mixture was cooled to 25 °C, quenched with saturated sodium chloride (10 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in dimethyl sulfoxide (2 mL), and then carbonyl diimidazole (24.0 mg, 0.15 mmol) and 1,8-diazabicycloundec-7-ene (37.6 mg, 0.25 mmol) were added. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated sodium chloride (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to give compound 29-4 (35 mg, 54%) as a brown solid.

[0660] ESI-MS (m / z): [M+H] + = 529.7.

[0661] Step D: 5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1-(6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-oxabicyclo[3.1.0]hex-6-yl)-1H-indole-2-carboxylic acid (29-5)

[0662]

[0663] To a mixture of compound 29-4 (35.0 mg, 0.66 mmol) in 2-methoxyethanol (2 mL) was added potassium hydroxide (392.8 mg, 7.0 mmol). The reaction mixture was heated to 100 °C and stirred for 7 h. The reaction mixture was cooled to 0 °C, and diluted HCl (6 M) (pH = 2) was added slowly. The reaction mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (10% methanol / dichloromethane) to give compound 29-5 (18.2 mg, 52%) as a brown solid.

[0664] ESI-MS (m / z): [M+H] + = 440.6.

[0665] Step E: 3-(6-(5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-3-oxabicyclo[3.1.0]hex-6-yl)-1,2,4-oxadiazol-5(4H)-one (29)

[0666]

[0667] To a mixture of compound 29-5 (8.0 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL) were added 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.4 mg, 0.03 mmol), intermediate I-1 (8.9 mg, 0.02 mmol) and N,N-diisopropylethylamine (4.7 mg, 0.04 mmol), and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (30% 0 - 30% ethyl acetate / petroleum ether) to give compound 29 (1.5 mg, 9%) as a brown solid.

[0668] LC-MS: ESI-MS (m / z): [M+H] + = 911.5

[0669] 1 H NMR (400 MHz, CDCl 3 -d 6 ): δ 8.75 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.53 (s, 2H), 7.26 (s, 1H) 7.15 (d, J = 6.0 Hz, 1H), 6.73 (s, 1H), 6.31 (s, 1H), 6.10 (s, 1H), 5.78 (s, 1H), 4.73 (d, J = 9.2 Hz, 1H), 4.12 (s, 3H), 4.07 - 3.79 (m, 6H), 3.59 (s, 1H), 3.04 (s, 2H), 2.78 - 2.61 (m, 2H), 2.37 - 2.20 (m, 10H), 1.77 - 1.72 (m, 3H) 1.35 (s, 8H) Table 3a provides the structures of intermediate compounds A-1 to A-4.

[0670]

[0671] Example 1a: 1-[(1R,5S,6S)-3-[(tert-Butoxy)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hex-6-yl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indole-2-carboxylic acid (A-1)

[0672]

[0673] Step A: (3S,4R)-3,4-Dihydroxypyrrolidine-1-carboxylic acid tert-butyl ester (A-1-2)

[0674] To a mixture of A-1-1 (50.00 g, 295.60 mmol) in acetone / water (500 mL / 125 mL) was added an aqueous solution of N-methylmorpholine N-oxide (208 mL, 104.00 g, 443.50 mmol, 50 wt%) and potassium osmate dihydrate (2.80 g, 8.90 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was washed with saturated sodium sulfite (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give A-1-2 (51.60 g, 85%) as a brown oil.

[0675] ESI-MS (m / z): [M-H] - = 202.1

[0676] Step B: tert-Butyl (3aR,6aS)-tetrahydro-5H-[1,3,2]dioxathiololo[4,5-c]pyrrole-5-carboxylate 2-oxide (A-1-3)

[0677] At 0 °C, sulfuryl chloride (25 mL, 381.00 mmol) was added dropwise to a mixture of A-1-2 (51.60 g, 254.42 mmol) and triethylamine (141 mL, 1016.00 mmol) in dichloromethane (1550 mL). The reaction mixture was stirred at 25 °C for 2 h and quenched with saturated brine (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give A-1-3 (63.00 g) as a brown oil.

[0678] ESI-MS (m / z): [M+H] + = 250.2

[0679] Step C: tert-Butyl (3aR,6aS)-tetrahydro-5H-[1,3,2]dioxathiololo[4,5-c]pyrrole-5-carboxylate 2,2-dioxide (A-1-4)

[0680] At 0 °C, sodium periodate (65.00 g, 303.50 mmol) and ruthenium(III) chloride (1.10 g, 5.06 mmol) were added to a mixture of A-1-3 (63.00 g, 252.72 mmol) in acetonitrile / water (630 mL / 630 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction solution was quenched with water (200 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give A-1-4 (40.0 g, 59%) as a white solid.

[0681] ESI-MS (m / z): [M+H] + = 266.2

[0682] Step D: Ethyl 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (A-1-7)

[0683] Under a nitrogen atmosphere, trimethylchlorosilane (1.65 g, 15.2 mmol) and 1,2-dibromoethane (2.86 g, 15.2 mmol) were added to a suspension of zinc powder (9.00 g, 138.5 mmol) in N,N-dimethylformamide (28 mL). The reaction mixture was stirred at 25 °C for 5 min. A solution of compound A-1-6 (25.00 g, 104.1 mmol) in N,N-dimethylformamide (42 mL) was added and the mixture was stirred at 25 °C for 20 min. Under a nitrogen atmosphere, palladium acetate (780 mg, 3.5 mmol), (4-N,N-dimethylamino)phenylbis-tert-butyl (1.84 g, 6.93 mmol) and A-1-5 (9.31 g, 34.7 mmol) were added, and the mixture was heated to 55 °C and maintained for 2 h. The reaction mixture was cooled to 25 °C, quenched with diluted HCl (4 M), diluted with water (100 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (0-15%, ethyl acetate / petroleum ether) to give A-1-7 (9.12 g, 87%) as a white solid.

[0684] ESI-MS (m / z): [M+H]+ = 302.1.

[0685] Step E: Ethyl (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (A-1-8)

[0686] A-1-7 (16.70 g) was separated by preparative chiral HPLC (SFC) to give A-1-8 (8.20 g) as a white solid and its enantiomer (7.28 g). Retention time of A-1-8: 15.980 min, retention time of enantiomer: 9.534 min.

[0687] The separation conditions were as follows:

[0688] Instrument: Kep300

[0689] Column: Chiral ART Amylose KBN 5 μm, column temperature: 25 °C

[0690] Solvent: ethanol = 100 (V)

[0691] Flow rate: 100 mL / min

[0692] The analysis conditions were as follows:

[0693] Apparatus: Shimadzu LC 20CNZ, equipped with UV detector SPD M20A

[0694] Column: Chiral ART Amylose KBN(5μm), 0.46 cm I.D.×25 cm L

[0695] Column temperature: 25 °C

[0696] Solvent: ethanol = 100(V)

[0697] Flow rate: 1.0 mL / min

[0698] Step F: Ethyl (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (A-1-9)

[0699] At 0 °C, sodium hydride (0.24 g, 9.96 mmol) and chloroacetonitrile (1.00 g, 13.28 mmol) were added to a mixture of A-1-8 (2.00 g, 6.64 mmol) in N,N-dimethylformamide (40 mL). The reaction mixture was stirred at 25 °C for 16 h, quenched with water (40 mL), acidified with HCl to pH 5, and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated brine (10 mL×2) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give A-1-9 (2.00 g, 89%) as a white solid.

[0700] ESI-MS (m / z): [M+H] + = 341.4

[0701] Step G: Ethyl 1-[(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hex-6-yl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indole-2-carboxylate (A-1-10)

[0702] Under a nitrogen atmosphere and at 0 °C, potassium bis(trimethylsilyl)amide (1 M in THF, 5.47 mL, 5.47 mmol) was slowly added to a mixture of A-1-9 (690.0 mg, 2.03 mmol), A-1-4 (1.10 g, 4.05 mmol), and 1,3-dimethyl-perhydro-2-pyrimidinone (1.10 g, 8.11 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at 0 °C for 1 h, quenched with saturated ammonium chloride (10 mL), and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated brine (10 mL × 2) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 95 / 5) to give A-1-10 (400.0 mg, 39%) as a yellow solid.

[0703] ESI-MS (m / z): [M + H - Boc] + = 408.3.

[0704] Step H: 1-[(1R,5S,6S)-3-[(tert-Butoxy)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hex-6-yl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indole-2-carboxylic acid (A-1)

[0705] Lithium hydroxide monohydrate (288.0 mg, 6.85 mmol) was added to a mixture of A-1-10 (400.0 mg, 0.79 mmol) in tetrahydrofuran / ethanol / water (5 mL / 1 mL / 1 mL). The reaction mixture was stirred at 50 °C for 3 h and cooled to 0 °C, acidified to pH 4 with HCl (1 M), and extracted with ethyl acetate (15 mL × 2). The combined organic layers were concentrated to dryness under reduced pressure to give A-1 (330.0 mg, 87%) as an off-white solid.

[0706] ESI-MS (m / z): [M - H] - = 478.2.

[0707] Example 2a: 1-[(1R,5S,6S)-3-[(tert-Butoxy)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxan-4-yl)-1H-indole-2-carboxylic acid (A-2)

[0708]

[0709] Step A: Ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (A-2-3)

[0710] Under a nitrogen atmosphere, a mixture of A-2-1 (8.00 g, 29.84 mmol), A-2-2 (7.50 g, 35.91 mmol), dichlorobis[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (2.20 g, 2.98 mmol) and potassium carbonate (8.20 g, 59.68 mmol) in 1,4-dioxane / water (160 mL / 40 mL) was stirred at 85 °C for 3 h. The reaction mixture was cooled to 25 °C, quenched with water (200 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give A-2-3 (9.6 g) as a yellow solid.

[0711] ESI-MS (m / z): [M+H] + = 271.9.

[0712] Step B: Ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (A-2-4)

[0713] Under a hydrogen atmosphere, a mixture of A-2-3 (9.60 g, 35.38 mmol) and Pd / C (0.96 g, 10 wt%) in methanol / tetrahydrofuran (30 mL / 90 mL) was stirred at 25 °C for 16 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated to dryness under reduced pressure to give A-2-4 (7.30 g) as a grey solid.

[0714] ESI-MS (m / z): [M+H] + = 274.0.

[0715] Step C: Ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (A-2-5)

[0716] At 0 °C, sodium hydride (2.00 g, 49.56 mmol) was added to a mixture of A-2-4 (9.00 g, 33.04 mmol) in N,N-dimethylformamide (180 mL). The reaction mixture was stirred at 0 °C for 0.5 h. Chloroacetonitrile (5.00 g, 66.08 mmol) was added. The reaction mixture was stirred at 75 °C for 15 h and cooled to 25 °C, quenched with water (200 mL), and extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was triturated with a mixture of petroleum ether and ethyl acetate (30 mL / 30 mL) for 1 h and filtered. The filter cake was dried to give A-2-5 (8.30 g, 80%) as an off-white solid.

[0717] ESI-MS (m / z): [M+H] + = 313.2.

[0718] Step D: Ethyl 1-[(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-5-(oxan-4-yl)-1H-indole-2-carboxylate (A-2-6)

[0719] Under a nitrogen atmosphere and at 0 °C, potassium bis(trimethylsilyl)amide (1 M in THF, 43.22 mL, 43.22 mmol) was slowly added to a mixture of A-2-5 (5.00 g, 16.01 mmol) and A-1-4 (6.40 g, 24.01 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 0 °C for 0.5 h, quenched with water (200 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 75 / 25) to give A-2-6 (2.60 g, 34%) as a pale yellow solid.

[0720] ESI-MS (m / z): [M-H] - = 480.6.

[0721] Step E: 1-[(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hexan-6-yl]-5-(oxan-4-yl)-1H-indole-2-carboxylic acid (A-2)

[0722] Lithium hydroxide monohydrate (288.0 mg, 12.03 mmol) was added to a mixture of A-2-6 (300 mg, 0.63 mmol) in tetrahydrofuran / methanol / water (5 mL / 3 mL / 1 mL). The reaction mixture was stirred at 25 °C for 1 h, quenched with water (10 mL), acidified to pH 4 with HCl (1 M), and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate =

[0723] 60 / 40) to give A-2 (80.0 mg, 85%) as a pale yellow solid.

[0724] ESI-MS (m / z): [M-H] - = 452.5.

[0725] Example 3a: 1-[(1R,5S,6S)-3-[(tert-Butoxy)carbonyl]-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxan-4-yl)-1H-indole-2-carboxylic acid (A-3)

[0726]

[0727] Step A: Ethyl 1-[(1R,5S,6S)-3-[(tert-Butoxy)carbonyl]-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxan-4-yl)-1H-indole-2-carboxylate (A-3-1)

[0728] Under a nitrogen atmosphere, a mixture of A-2-6 (500.0 mg, 1.04 mmol), trimethylsilyl azide (5 mL), and tetrabutylammonium fluoride (136.3 mg, 0.52 mmol) in N,N-dimethylformamide (2 mL) was stirred at 120 °C for 16 h. The reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 2) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 99 / 1) to give A-3-1 (100.0 mg, yield: 18%) as a yellow solid.

[0729] ESI-MS (m / z): [M+H] + = 523.3.

[0730] Step B: 1-[(1R,5S,6S)-3-[(tert-Butoxy)carbonyl]-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxan-4-yl)-1H-indole-2-carboxylic acid (A-3)

[0731] To a mixture of A-3-1 (0.10 g, 0.19 mmol) in tetrahydrofuran / ethanol / water (5 mL / 1 mL / 1 mL) was added lithium hydroxide monohydrate (288.0 mg, 6.85 mmol). The reaction mixture was stirred at 50 °C for 3 h and cooled to 25 °C, acidified to pH 4 with HCl (1 M), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give A-3 (100.0 mg) as an off-white solid.

[0732] ESI-MS (m / z): [M-H] - = 493.2.

[0733] 1 1H NMR (400 MHz, DMSO-d6) δ 7.85 (t, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.40–7.33 (m, 1H), 7.17 (d, J = 7.5 Hz, 1H), 3.98–3.93 (m, 2H), 3.92–3.85 (m, 2H), 3.57–3.41 (m, 4H), 2.90–2.77 (m, 1H), 2.76–2.64 (m, 2H), 1.76–1.66 (m, 4H), 1.24 (d, J = 8.2 Hz, 9H).

[0734] Example 4a: 5-[(4S)-2,2-Dimethyloxan-4-yl]-1-[(1R,5S,6R)-3,3-dioxido-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3λ 6 -thiatricyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid (A-4)

[0735]

[0736] Step A: (3aS,6aS)-2,2-Dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (A-4-2)

[0737] Under a nitrogen atmosphere, concentrated sulfuric acid (9.69 mL) was slowly added to a mixture of A-4-1 (51.00 g, 431.87 mmol) in acetone (663 mL). The reaction mixture was stirred at 25 °C for 2 h and cooled to 0 °C, quenched with saturated sodium bicarbonate (500 mL), and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give A-4-2 (65.00 g) as a white solid.

[0738] ESI-MS (m / z): [M-H] - = 157.3.

[0739] Step B: ((4S,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (A-4-3)

[0740] At 0 °C, lithium aluminum hydride (31.20 g, 822.13 mmol) was slowly added to a mixture of A-4-2 (65.00 g, 411.00 mmol) in tetrahydrofuran (650 mL). The reaction mixture was stirred at 25 °C for 1 h and cooled to 0 °C. Sodium sulfate decahydrate (322 g, 1.00 mol) was added. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to give A-4-3 (48.00 g) as a colorless oil.

[0741] ESI-MS (m / z): [M-H] - = 161.1.

[0742] Step C: ((4S,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene) dimethanesulfonate (A-4-4)

[0743] At 0 °C, triethylamine (193.20 g, 1909.02 mmol) and methanesulfonyl chloride (109.30 g, 954.51 mmol) were added to a mixture of A-4-3 (51.60 g, 318.17 mmol) in dichloromethane (516 mL). The reaction mixture was stirred at 0 °C for 1 h and quenched with saturated brine (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give A-4-4 (101.00 g) as a yellow oil.

[0744] ESI-MS (m / z): [M+H] + = 339.2.

[0745] Step D: (3aR,6aS)-2,2-Dimethyltetrahydrothieno[3,4-d][1,3]dioxolane (A-4-5)

[0746] Under a nitrogen atmosphere, sodium sulfide (29.70 g, 380.7 mmol) was added to a mixture of A-4-4 (101.00 g, 317.25 mmol) in N,N-dimethylformamide (1000 mL). The reaction mixture was stirred at 100 °C for 8 h, cooled to 25 °C, quenched with water (1500 mL), and extracted with ethyl acetate (500 mL × 3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give A-4-5 (26.00 g, 51%) as a white solid.

[0747] ESI-MS (m / z): [M+H] + = 161.3.

[0748] Step E: (3R,4S)-tetrahydrothiophene-3,4-diol (A-4-6)

[0749] To a mixture of A-4-5 (26.00 g, 162.27 mmol) in methanol (100 mL) was added glacial acetic acid (200 mL). The reaction mixture was stirred under reflux for 20 h, cooled to 25 °C, and concentrated to dryness under reduced pressure to give A-4-6 (18.00 g) as a yellow solid.

[0750] ESI-MS (m / z): [M-H] - = 119.0.

[0751] Step F: (3aR,6aS)-tetrahydrothieno[3,4-d][1,3,2]dioxathiolane-2,2-dioxide (A-4-7)

[0752] At 0 °C, sulfuryl chloride (8.80 g, 64.91 mmol) was slowly added to a mixture of A-4-6 (6.00 g, 49.93 mmol) and triethylamine (25.26 g, 249.65 mmol) in ethyl acetate (600 mL). The reaction mixture was stirred at 25 °C for 2 h and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 75 / 25) to give A-4-7 (3.00 g, 33%) as a pale yellow solid.

[0753] ESI-MS (m / z): [M+H] + = 183.1.

[0754] Step G: Ethyl 1-[(1R,5S,6R)-6-cyano-3-thiabicyclo[3.1.0]hex-6-yl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indole-2-carboxylate (A-4-9)

[0755] Under a nitrogen atmosphere at -40 °C, potassium bis(trimethylsilyl)amide (1 M in THF, 4.41 mL) was slowly added to a mixture of A-4-8 (500.0 mg, 1.47 mmol) and A-4-7 (535.3 mg, 2.94 mmol) in tetrahydrofuran / 1,3-dimethyl-perhydro-2-pyrimidinone (3 mL / 3 mL). The reaction mixture was stirred at -40 °C for 2 h, quenched with water (10 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give A-4-9 (330.0 mg, 53%) as a pale yellow solid.

[0756] ESI-MS (m / z): [M+H]+ = 425.0.

[0757] Step H: Ethyl 5-[(4S)-2,2-dimethyloxan-4-yl]-1-[(1R,5S,6R)-6-(N'-hydroxyamidinyl)-3-thiabicyclo[3.1.0]hexan-6-yl]-1H-indole-2-carboxylate (A-4-10)

[0758] To a mixture of A-4-9 (441.0 mg, 1.04 mmol) in ethanol (8 mL) was added hydroxylamine hydrochloride (721.8 mg, 10.39 mmol) and N,N-diisopropylethylamine (1.30 g, 10.39 mmol). The reaction mixture was stirred at 65 °C for 16 h, cooled to 25 °C, and concentrated to dryness under reduced pressure. The residue was treated with saturated brine (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give A-4-10 (472.0 mg) as a light brown solid.

[0759] ESI-MS (m / z): [M+H] + = 458.2.

[0760] Step I: Ethyl 5-[(4S)-2,2-dimethyloxan-4-yl]-1-[(1R,5S,6R)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-thiabicyclo[3.1.0]hexan-6-yl]-1H-indole-2-carboxylate (A-4-11)

[0761] To a mixture of A-4-10 (472.0 mg, 1.03 mmol) in dimethyl sulfoxide (6.00 mL) was added N,N'-carbonyldiimidazole (334.9 mg, 2.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (393.1 mg, 2.58 mmol). The reaction mixture was stirred at 25 °C for 0.5 h, quenched with saturated sodium chloride (10 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine (10 mL) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 98 / 2) to give A-4-11 (346.0 mg, 69%) as a white solid.

[0762] ESI-MS (m / z): [M+H] + = 484.2.

[0763] Step J: Ethyl 5-[(4S)-2,2-dimethyloxan-4-yl]-1-[(1R,5S,6R)-3,3-dioxido-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3λ 6 -thiatricyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylate (A-4-12)

[0764] At 0 °C, m-chloroperbenzoic acid (435.8 mg, 2.15 mmol) was added to a mixture of A-4-11 (346.0 mg, 0.72 mmol) in methanol / dichloromethane (3 mL / 6 mL). The reaction mixture was stirred at 0 °C for 0.5 h and at 30 °C for 4 h. The reaction mixture was quenched with saturated sodium sulfite (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 98 / 2) to give A-4-12 (327.0 mg, 89%) as a yellow solid.

[0765] ESI-MS (m / z): [M+H] + = 516.0.

[0766] Step K: 5-[(4S)-2,2-dimethyloxan-4-yl]-1-[(1R,5S,6R)-3,3-dioxido-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3λ 6 -thiatricyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid (A-4)

[0767] Lithium hydroxide monohydrate (66.5 mg, 1.59 mmol) was added to a mixture of A-4-12 (327.0 mg, 0.63 mmol) in tetrahydrofuran / water (5 mL / 2.5 mL). The reaction mixture was stirred at 40 °C for 16 h and cooled to 25 °C, quenched with hydrochloric acid (1 M) to pH 3, and extracted with ethyl acetate (5 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to give A-4 (105.0 mg, 34%) as a white solid.

[0768] ESI-MS (m / z): [M-H] - = 486.0

[0769] 1 H NMR (400 MHz, CDCl 3)δ 10.55 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.52 (s, 1H), 7.38 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 4.07 (d, J = 12.8 Hz, 1H), 3.93 - 3.74 (m, 3H), 3.10 (d, J = 15.6 Hz, 2H), 3.05 - 2.98 (m, 1H), 2.94 - 2.86 (m, 1H), 2.70 - 2.62 (m, 1H), 1.73 (d, J = 15.6 Hz, 3H), 1.63 (t, J = 12.8 Hz, 1H), 1.35 (s, 3H), 1.29 (s, 3H).

[0770] Table 3b provides the structures of intermediate compounds B-1 to B-13.

[0771] Table 3b:

[0772]

[0773]

[0774]

[0775]

[0776] Example 5a: (S)-1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (B-1)

[0777]

[0778] Step A: Di-tert-butyl 1-(4-fluoro-3,5-dimethylphenyl)hydrazine-1,2-dicarboxylate (B-1-2)

[0779] At -70 °C, n-butyllithium (85.1 mL, 2.5 M hexane solution, 212.76 mmol) was added dropwise to a mixture of B-1-1 (45.00 g, 221.62 mmol) in tetrahydrofuran (450 mL) and the mixture was stirred for 1 h. Then, di-tert-butyl azodicarboxylate (45.93 g, 199.46 mmol) was added dropwise at -40 °C and the mixture was stirred for 0.5 h. The reaction mixture was warmed to 25 °C over 1 h and quenched with saturated ammonium chloride solution (460 mL). The reaction mixture was extracted with heptane (230 mL). The organic layer was separated and concentrated. Heptane (70 mL) was added and the mixture was heated to 70 °C to facilitate dissolution. The solution was cooled to 25 °C and a white solid precipitated over 1 h. The precipitate was collected by filtration, washed with heptane (23 mL) and dried to give B-1-2 (42.00 g, 53%) as a white solid.

[0780] 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.56 (s, 1H), 7.07–6.96 (m, 2H), 2.19 (s, 6H), 1.50–1.37 (m, 18H).

[0781] Step B: tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (B-1-3)

[0782] Methanesulfonic acid (22.78 g, 237 mmol) was added to a mixture of B-1-2 (42.00 g, 118.50 mmol) in N-methyl-2-pyrrolidone (126 mL) and the mixture was stirred at 80 °C for 7 h. The reaction mixture was cooled to 25 °C; toluene (252 mL), potassium carbonate (18.02 g, 130.35 mmol) and water (252 mL) were added. The reaction mixture was stirred at 25 °C for 10 min. The organic layer was separated and a solution of tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (27.82 g, 116.74 mmol) in toluene (126 mL), pyridine hydrochloride (1.35 g, 11.67 mmol) and toluene (84 mL) were added thereto. The reaction mixture was stirred at 90 °C for 1 h and cooled to 25 °C. The reaction mixture was washed with aqueous sodium hydroxide solution (252 mL, 1 M). The organic layer was separated and concentrated under reduced pressure to give B-1-3 (34.80 g, 80%) as a brown oil.

[0783] ESI-MS (m / z): [M+H] + = 374.9.

[0784] 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.22 (d, J = 6.4 Hz, 2H), 5.18 (s, 2H), 5.07 (d, J = 43.4 Hz, 1H), 4.24–4.02 (m, 1H), 3.14–2.90 (m, 1H), 2.48–2.38 (m, 2H), 2.25 (d, J = 1.2 Hz, 6H), 1.43 (s, 9H), 1.24 (d, J = 6.0 Hz, 3H).

[0785] Step C: tert-Butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (B-1-4)

[0786] To a mixture of B-1-3 (11.00 g, 29.38 mmol) and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (17.56 g, 88.14 mmol) in N,N-dimethylacetamide (110 mL) was added potassium tert-butoxide (19.78 g, 176.28 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with water (200 mL) at 0 °C and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with saturated sodium chloride (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 - 5% MeOH / dichloromethane) to give compound B-1-4 (14.00 g, 94%) as a yellow solid.

[0787] ESI-MS (m / z): [M + H] + = 505.9.

[0788] Step D: tert-Butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (B-1-5)

[0789] To a mixture of B-1-4 (14.00 g, 27.69 mmol) in tetrahydrofuran (140 mL) was added methanesulfonic acid (2.66 g, 27.69 mmol), and the mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to 25 °C, and a solution of potassium phosphate (2.35 g, 11.08 mmol) in water (56 mL) and di-tert-butyl dicarbonate (4.83 g, 22.15 mmol) were added. The resulting mixture was stirred at 25 °C for 1 h, diluted with water (150 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated sodium chloride (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (20 - 30% EA / PE) to give B-1-5 (8.00 g, 65%) as a yellow solid.

[0790] ESI-MS (m / z): [M+H] + = 442.2.

[0791] Step E: tert-Butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (B-1-6)

[0792] To a mixture of B-1-5 (1.00 g, 2.27 mmol) and Compound 1-13 (778 mg, 3.40 mmol) in N-methyl-2-pyrrolidone (10 mL) were added copper(I) iodide (216 mg, 1.14 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (323 mg, 2.27 mmol), and potassium carbonate (941 mg, 6.81 mmol). The reaction was stirred at 120 °C for 16 h under a nitrogen atmosphere. The reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 - 62%, ethyl acetate / petroleum ether) to give B-1-6 (1.10 g, 82%) as a yellow solid.

[0793] ESI-MS (m / z): [M+H] + = 590.0.

[0794] Step F: (S)-1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (B-1)

[0795] To a mixture of B-1-6 (450 mg) in dichloromethane (4.5 mL) was added HCl (1.9 mL, 4 M 1,4-dioxane solution), and the mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was redissolved in ethyl acetate and washed with saturated NaHCO 3 solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give B-1 (350 mg, 94%) as a yellow solid.

[0796] ESI-MS (m / z): [M+H] + = 489.9.

[0797] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (s, 1H), 7.64–7.58 (m, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 6.2 Hz, 2H), 7.03–6.98 (m, 1H), 6.84 (s, 1H), 4.10 (s, 3H), 3.93–3.85 (m, 1H), 3.21–3.15 (m, 1H), 2.86–2.79 (m, 1H), 2.66–2.57 (m, 2H), 2.26–2.16 (m, 7H), 1.13 (d, J = 6.6 Hz, 3H).

[0798] Example 6: (S)-1-(2-(3-Chloro-4-fluoro-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (B-2)

[0799] The title compound was obtained by following a method similar to Example 5a using 5-bromo-1-chloro-2-fluorotoluene in place of 4-bromo-2,6-dimethylfluorobenzene.

[0800] ESI-MS (m / z): [M+H] + = 510.2.

[0801] 1 H NMR (400 MHz, DMSO-d 6)δ8.28(s,1H),7.62(d,J=9.0Hz,1H),7.43-7.30(m,3H),7.08(d,J=3.3Hz,1H),6.92(d,J=3.0Hz,1H),4.10(s,3H),4.04(q,J=6.6Hz,1H),3.33-3.24(m,1H),2.98-2.89(m,1H),2.77-2.66(m,2H),2.31(d,J=2.1Hz,3H),1.24(d,J=6.9Hz,1H),1.19(d,J=6.6Hz,3H).

[0802] Example 7: (S)-2-Fluoro-5-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-3-methylbenzonitrile (B-3)

[0803] The title compound was obtained by replacing 4-bromo-2,6-dimethylfluorobenzene with 5-bromo-1-cyano-2-fluorotoluene in a similar manner to Example 5a.

[0804] ESI-MS(m / z): [M+H] + = 501.2.

[0805] 1 1H NMR(400MHz, DMSO-d 6 )δ8.11(s,1H),7.65-7.59(m,1H),7.51-7.47(m,1H),7.46-7.37(m,1H),7.28-7.22(m,1H),6.64-6.60(m,1H),6.33-6.28(m,1H),4.22-4.15(m,1H),4.10(s,3H),3.48-3.38(m,1H),3.20-3.01(m,1H),2.93-2.77(m,2H),2.70-2.45(m,1H),2.36-2.32(m,3H),1.36(d,J = 6.6Hz,3H).

[0806] Example 8: (S)-1-(2-(3,4-Difluoro-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (B-4)

[0807] The title compound was obtained by substituting 5-bromo-1,2-difluoro-3-methylbenzene for 4-bromo-2,6-dimethylfluorobenzene in a similar manner to Example 5a.

[0808] ESI-MS (m / z): [M+H] + = 493.9.

[0809] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.31 - 7.20 (m, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.92 (s, 1H), 4.10 (s, 3H), 3.94 - 3.85 (m, 1H), 3.26 - 3.13 (m, 1H), 2.91 - 2.74 (m, 1H), 2.62 (s, 2H), 2.36 (s, 1H), 2.31 (d, J = 1.8 Hz, 3H), 1.12 (d, J = 6.6 Hz, 3H).

[0810] Example 9: (S)-1-(4-Fluoro-1-(methyl-d3)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (B-5)

[0811]

[0812] Step A: 5-Bromo-4-fluoro-1-(methyl-d3)-1H-indazole (B-5-2)

[0813] Sodium hydride (112 mg, 2.80 mmol) was added to a mixture of B-5-1 (0.5 g, 2.33 mmol) in N,N-dimethylformamide (3.5 mL). The reaction mixture was stirred at 25 °C for 10 min. Then iodomethane-d3 (0.41 g, 2.80 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h, quenched with saturated ammonium chloride (2 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give B-5-2 (350 mg, 65%) as a white solid.

[0814] ESI-MS (m / z): [M+H] + = 232.9.

[0815] Step B: tert-Butyl (S)-3-(3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (B-5-3)

[0816] Under a nitrogen atmosphere, a mixture of B-1-5 (450 mg, 1.02 mmol), B-5-2 (350 mg, 1.53 mmol), potassium carbonate (422 mg, 3.06 mmol), trans-(1S,2S)-N,N'-dimethylcyclohexane-1,2-diamine (145 mg, 1.02 mmol), and copper(I) iodide (97 mg, 0.51 mmol) in N-methylpyrrolidone (5 mL) was stirred at 120 °C for 8 h and then cooled to 25 °C. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 3) to give B-5-3 (500 mg, 83%) as a light gray solid.

[0817] ESI-MS (m / z): [M+H]+ = 592.9.

[0818] Step C: (S)-1-(4-Fluoro-1-(methyl-d3)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (B-5)

[0819] HCl (4 M 1,4-dioxane solution, 2 mL) was added to a mixture of B-5-3 (200 mg, 0.34 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at 25 °C for 4 h and concentrated to dryness under reduced pressure to give B-5 (200 mg, 98%) as a light brown solid.

[0820] ESI-MS (m / z): [M+H] + = 602.9.

[0821] 1 H NMR (400 MHz, DMSO-d 6)δ 10.13 (s, 1H), 9.55 - 9.39 (m, 1H), 8.29 (s, 1H), 7.65 - 7.60 (m, 1H), 7.45 - 7.38 (m, 1H), 7.16 (d, J = 6.2 Hz, 2H), 7.08 - 7.04 (m, 1H), 6.88 - 6.83 (m, 1H), 4.63 - 4.52 (m, 1H), 3.67 - 3.55 (m, 1H), 3.12 - 2.92 (m, 2H), 2.27 - 2.20 (m, 6H), 1.43 (d, J = 6.8 Hz, 3H).

[0822] Example 10: (S)-1-(2-(3-Chloro-4-fluoro-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (B-6)

[0823] The title compound was obtained by replacing 4-bromo-2,6-dimethylfluorobenzene with 5-bromo-1-chloro-2-fluorotoluene in a similar manner to Example 5a.

[0824] ESI-MS (m / z): [M + H] + = 513.2.

[0825] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.42 - 7.28 (m, 3H), 7.11 - 7.06 (m, 1H), 6.93 (s, 1H), 4.01 - 3.89 (m, 1H), 3.35 - 3.05 (m, 1H), 2.92 - 2.75 (m, 1H), 2.72 - 2.56 (m, 2H), 2.38 - 2.21 (m, 3H), 1.16 (d, J = 6.4 Hz, 3H).

[0826] Example 11: (S)-2-Fluoro-5-(3-(3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-3-methylbenzonitrile (B-7)

[0827] The title compound was obtained by replacing 4-bromo-2,6-dimethylfluorobenzene with 5-bromo-1-cyano-2-fluorotoluene in a similar manner to Example 5a.

[0828] ESI-MS (m / z): [M+H] + = 504.4

[0829] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.65 - 7.60 (m, 1H), 7.53 - 7.48 (m, 1H), 7.45 - 7.39 (m, 1H), 7.27 - 7.24 (m, 1H), 6.63 (d, J = 1.6 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H), 4.28 - 4.20 (m, 1H), 3.53 - 3.39 (m, 1H), 3.23 - 3.07 (m, 1H), 3.00 - 2.87 (m, 2H), 2.87 - 2.82 (m, 1H), 2.34 (d, J = 1.6 Hz, 3H), 1.49 - 1.43 (m, 1H), 1.40 (d, J = 6.4 Hz, 2H).

[0830] Example 12: (S)-1-(2-(3,4-Difluoro-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (B-8)

[0831] The title compound was obtained by replacing 4-bromo-2,6-dimethylfluorobenzene with 5-bromo-1,2-difluoro-3-methylbenzene in a similar manner to Example 5a.

[0832] ESI-MS (m / z): [M+H] + = 497.0

[0833] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (s, 1H), 7.62 (d, J = 9.5 Hz, 1H), 7.48 - 7.36 (m, 1H), 7.30 - 7.20 (m, 1H), 7.20 - 7.14 (m, 1H), 7.07 (d, J = 2.9 Hz, 1H), 6.92 (s, 1H), 4.02 - 3.89 (m, 1H), 3.26 - 3.15 (m, 1H), 2.93 - 2.78 (m, 1H), 2.70 - 2.55 (m, 2H), 2.31 (s, 3H), 1.14 (d, J = 6.5 Hz, 3H).

[0834] Example 13: (S)-1-(4-Fluoro-1-(methyl-d3)-1H-indazol-5-yl)-3-(2-(4-fluoro-3-methyl-5-(trifluoromethyl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (B-9)

[0835] The title compound was obtained by substituting 4-bromo-2,6-dimethylfluorobenzene with 4-fluoro-3-bromo-5-(trifluoromethyl)bromobenzene in a similar manner to Example 5a.

[0836] ESI-MS (m / z): [M+H] + = 547.2.

[0837] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (s, 1H), 7.80 - 7.71 (m, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.53 - 7.46 (m, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.13 - 7.06 (m, 1H), 7.00 - 6.93 (m, 1H), 4.10 - 3.98 (m, 1H), 3.40 - 3.23 (m, 2H), 3.00 - 2.87 (m, 1H), 2.79 - 2.64 (m, 2H), 2.36 (d, J = 1.5 Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H).

[0838] Example 14: (S)-1-(4-Fluoro-1-(methyl-d3)-1H-indazol-5-yl)-3-(2-(4-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (B-10)

[0839] The title compound was obtained by substituting 4-bromo-2,6-dimethylfluorobenzene with 5-bromo-2-fluorotoluene in a similar manner to Example 5a.

[0840] ESI-MS (m / z): [M+H] + = 479.2.

[0841] 1 H NMR (400 MHz, DMSO-d 6)δ8.11(s,1H),7.50-7.39(m,1H),7.34 -7.30(m,1H),7.26-7.23(m,1H),7.23-7.19(m,1H),7.04(t,J=9.0Hz,1H),6.55-6.50(m,1H),6.21(d,J=3.3Hz,1H),4.35-4.25(m,1H),3.54-3.42(m,1H),3.22-3.09(m,1H),3.05-2.78(m,3H),2.29(d,J=1.5Hz,3H),1.42(d,J=6.6Hz,3H).

[0842] Example 15: (S)-1-(2-(3-chloro-4-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (B-11)

[0843] The title compound was obtained by substituting 3-chloro-4-fluorobromobenzene for 4-bromo-2,6-dimethylfluorobenzene and following a method similar to that of Example 5a.

[0844] ESI-MS (m / z): [M+H] + = 499.2.

[0845] 1 1H NMR (400 MHz, DMSO-d 6 )δ8.28(s,1H),7.69–7.48(m,3H),7.48–7.30(m,2H),7.06(s,1H),6.94(s,1H),3.89(d,J=6.7Hz,1H),3.25–3.13(m,1H),2.91–2.76(m,1H),2.68–2.60(m,2H),2.45–2.30(m,1H),1.12(d,J=6.4Hz,3H).

[0846] Example 16: (S)-1-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (B-12)

[0847] The title compound was obtained by substituting 2,2,2-trifluoroethyl trifluoromethanesulfonate for deuterated iodomethane and following a method similar to that of Example 9.

[0848] ESI-MS (m / z): [M+H] + = 558.5.

[0849] Example 17: tert-Butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (B-13)

[0850]

[0851] Step A: Methyl 3-bromo-4-nitro-1H-pyrazole-5-carboxylate (B-13-2)

[0852] At 0 °C under a nitrogen atmosphere, cupric nitrate (II) trihydrate (13.51 g, 55.92 mmol) was added portionwise to a mixture of B-13-1 (9.55 g, 46.60 mmol) in trifluoroacetic anhydride and chloroform (50 mL / 50 mL). The reaction mixture was stirred at 25 °C for 3 h, cooled to 0 °C, quenched slowly with water (10 mL) and stirred for 2 h. The reaction mixture was extracted with dichloromethane (50 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give B-13-2 (13.33 g) as a yellow solid.

[0853] ESI-MS (m / z): [M+H] + = 250.0, 251.9.

[0854] Step B: Methyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-nitro-1H-pyrazole-5-carboxylate (B-13-3)

[0855] Under a nitrogen atmosphere at 0 °C, triphenylphosphine (20.08 g, 76.57 mmol) and diethyl azodicarboxylate (20.64 g, 102.1 mmol) were added to a mixture of B-13-2 (12.76 g, 51.05 mmol) and N-(tert-butoxycarbonyl)ethanolamine (8.23 g, 51.05 mmol) in tetrahydrofuran (130 mL). The reaction mixture was stirred at 0 °C for 2 h, quenched with water (50 mL), and extracted with ethyl acetate (80 mL × 3). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 1) to give B-13-3 (31.93 g) as a brown oil.

[0856] ESI-MS (m / z): [M+H] += 393.0, 395.0。

[0857] Step C: Methyl 1-(2-aminoethyl)-3-bromo-4-nitro-1H-pyrazole-5-carboxylate hydrochloride (B-13-4)

[0858] To a mixture of B-13-3 (8.73 g, 22.20 mmol) in dichloromethane (30 mL) was added HCl (4N 1,4-dioxane solution, 60 mL). The reaction mixture was stirred at 25 °C for 1 h and concentrated to give B-13-4 (12.07 g) as a white solid.

[0859] ESI-MS (m / z): [M+H] + = 293.0, 294.9。

[0860] Step D: 2-Bromo-3-nitro-6,7-dihydro-pyrazolo[1,5-a]pyridazin-4(5H)-one (B-13-5)

[0861] To a mixture of B-13-4 (12.07 g, 36.63 mmol) in 1,4-dioxane (120 mL) was added triethylamine (14.83 g, 146.52 mmol). The reaction mixture was stirred at 80 °C for 1 h and cooled to 25 °C, then concentrated to dryness under reduced pressure. The residue was triturated with methanol (30 mL), filtered and dried to give B-13-5 (1.88 g) as a white solid.

[0862] ESI-MS (m / z): [M+H] + = 260.9, 263.0。

[0863] Step E: 2-Bromo-3-nitro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridazine hydrochloride (B-13-6)

[0864] Under a nitrogen atmosphere, to a mixture of B-13-5 (1.78 g, 6.82 mmol) in tetrahydrofuran (18 mL) was added borane (1M THF solution, 17.1 mL, 17.10 mmol). The reaction mixture was stirred at 70 °C for 3 h, cooled to 25 °C, quenched with HCl (4M, 3 mL), and concentrated to dryness under reduced pressure. The residue was triturated with methanol (8 mL), filtered and dried to give B-13-6 (2.16 g) as a white solid.

[0865] ESI-MS (m / z): [M+H] + = 247.0, 249.0。

[0866] Step F: tert-Butyl 2-bromo-3-nitro-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (B-13-7)

[0867] To a mixture of B-13-6 (2.16 g, 8.73 mmol) in dichloromethane (30 mL) was added triethylamine (2.66 g, 26.19 mmol) and di-tert-butyl dicarbonate (2.48 g, 11.35 mmol). The reaction mixture was stirred at 25 °C for 1 h, quenched with water (1 mL), and extracted with ethyl acetate (30 mL × 2). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give B-13-7 (1.20 g) as a white solid.

[0868] ESI-MS (m / z): [M+H] + = 346.9, 348.8.

[0869] Step G: tert-Butyl 3-amino-2-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (B-13-8)

[0870] Under a nitrogen atmosphere, ammonium chloride (1.4 g, 26.0 mmol) and zinc powder (0.85 g, 13 mmol) were added to a mixture of B-13-7 (0.9 g, 2.6 mmol) in ethanol and water (10 mL / 10 mL). The reaction mixture was stirred under reflux for 3 h, cooled to 25 °C, quenched with water (10 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 3) to give B-13-8 (0.7 g, 82%) as a white solid.

[0871] ESI-MS (m / z): [M+H] + = 317.3.

[0872] Step H: tert-Butyl 2-bromo-3-((phenoxycarbonyl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (B-13-9)

[0873] At 0 °C, diisopropylethylamine (504.0 mg, 3.9 mmol) and phenyl chloroformate (396.9 mg, 2.54 mmol) were added to a mixture of B-13-8 (620.0 mg, 1.95 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at 25 °C for 2 h and concentrated to dryness under reduced pressure to give B-13-9 (600.0 mg, 80%) as a yellow solid.

[0874] ESI-MS (m / z): [M+H] + = 317.3

[0875] Step I: tert-Butyl 2-bromo-3-(3-(2,2-dimethoxyethyl)ureido)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (B-13-10)

[0876] To a mixture of B-13-9 (600.0 mg, 1.37 mmol) in pyridine (10 mL) was added 2,2-dimethoxyethylurea (288.1 mg, 2.74 mmol). The reaction mixture was stirred at 25 °C for 2 h, quenched with water (10 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give B-13-10 (600.0 mg) as a white solid.

[0877] ESI-MS (m / z): [M+H] + = 448.2

[0878] Step J: tert-Butyl 2-bromo-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (B-13-11)

[0879] At 0 °C, to a mixture of B-13-10 (580.0 mg, 1.29 mmol) in tetrahydrofuran (12 mL) was added methanesulfonic acid (99.2 mg, 1.03 mmol). The reaction mixture was stirred at 70 °C for 2 h, cooled to 25 °C, quenched with water (10 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give B-13-11 (480.0 mg) as a white solid.

[0880] ESI-MS (m / z): [M+H] + = 384.2

[0881] Step K: tert-Butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydro-1H-pyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (B-13-12)

[0882] Under a nitrogen atmosphere, 3,5-dimethyl-4-fluorophenylboronic acid (273.0 mg, 1.63 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (183.0 mg, 0.25 mmol), and potassium carbonate (518.3 mg, 3.75 mmol) were added to a mixture of B-13-11 (480.0 mg, 1.25 mmol) in 1,4-dioxane / water (8 mL / 2 mL). The reaction mixture was stirred at 100 °C for 3 h, cooled to 25 °C, quenched with water (5 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give B-13-12 (440.0 mg, 82%) as a white solid.

[0883] ESI-MS (m / z): [M+H] + = 428.3.

[0884] Step L: tert-Butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (B-13)

[0885] Under a nitrogen atmosphere, 5-bromo-4-fluoro-1-methylindazole (100.0 mg, 0.23 mmol), copper(I) iodide (4.4 mg, 0.02 mmol), trans-(1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (63.0 mg, 0.28 mmol), and potassium carbonate (48.0 mg, 0.35 mmol) were added to a mixture of B-13-12 (100.0 mg, 0.23 mmol) in N-methyl-2-pyrrolidone (2 mL). The reaction mixture was stirred at 130 °C for 3 h, cooled to 25 °C, quenched with water (3 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give B-13 (79.6 mg, yield: 59%) as a white solid.

[0886] ESI-MS (m / z): [M+H] + = 576.2.

[0887] 11H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.2 Hz, 2H), 7.01 (d, J = 2.8 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 4.55 (s, 2H), 4.18 (t, J = 5.6 Hz, 2H), 4.11 (s, 3H), 3.90 (t, J = 5.6 Hz, 2H), 2.22 (s, 6H), 1.45 (s, 9H).

[0888] Example 18: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-1)

[0889]

[0890] Step A: tert-Butyl (1R,5S,6S)-6-cyano-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-azabicyclo[3.1.0]hexane-3-carboxylate (C-1-1)

[0891] A-1 (330.0 mg, 0.69 mmol), B-1 (361.9 mg, 0.69 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (392.5 mg, 1.03 mmol), and diisopropylethylamine (266.8 mg, 2.06 mmol) in N,N-dimethylformamide (10 mL) were stirred at 25 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 99 / 1) to give C-1-1 (570.0 mg, 87%) as a yellow solid.

[0892] ESI-MS (m / z): [M+H] + = 951.5.

[0893] Step B: (1R,5S,6S)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-6-(N'-hydroxyamidinyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (C-1-2)

[0894] A mixture of C-1-1 (570.0 mg, 0.60 mmol), hydroxylamine hydrochloride (1.3 g, 17.98 mmol), and diisopropylethylamine (2.3 g, 17.98 mmol) in ethanol (10 mL) was stirred at 80 °C for 3 h, cooled to 25 °C, quenched with saturated ammonium chloride (10 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic layers were concentrated to dryness under reduced pressure to give C-1-2 (590.0 mg) as a pale solid.

[0895] ESI-MS (m / z): [M+H] + = 984.5.

[0896] Step C: tert-Butyl (1R,5S,6S)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (C-1-3)

[0897] A mixture of C-1-2 (590.0 mg, 0.60 mmol), N,N'-carbonyldiimidazole (194.3 mg, 1.20 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (228.1 mg, 1.5 mmol) in dimethyl sulfoxide (5 mL) was stirred at 25 °C for 3 h. The reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated brine (10 mL) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 99 / 1) to give C-1-3 (590.0 mg, 97%) as a pale solid.

[0898] ESI-MS (m / z): [M+H] + = 1010.4.

[0899] Step D: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-1)

[0900] HCl (2 mL of a 4 M 1,4-dioxane solution) was added to a mixture of C-1-3 (220.0 mg, 0.22 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at 25 °C for 1 h, quenched with saturated sodium bicarbonate (5 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give C-1 (190.0 mg) as a pale solid.

[0901] ESI-MS (m / z): [M+H] + = 910.4。

[0902] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.32 (m, 1H), 8.21 (m, 1H), 7.65 (m, 1H), 7.47 (m, 4H), 7.26 - 7.07 (m, 4H), 7.04 - 6.77 (m, 1H), 6.66 (s, 1H), 5.63 (m, 1H), 4.13 (m, 2H), 3.79 (m, 2H), 3.49 (m, 2H), 3.12 - 2.64 (m, 6H), 2.26 (m, 4H), 1.77 - 1.48 (m, 4H), 1.29 (m, 15H)。

[0903] Example 19: 3 - [(1R,5S,6S)-3 - Acetyl - 6 - {5 - [(4S)-2,2 - Dimethyloxan - 4 - yl]-2 - [(4S)-3 - [3 - (4 - Fluoro - 1 - methyl - 1H - indazol - 5 - yl)-2 - oxo - 2,3 - dihydro - 1H - imidazol - 1 - yl]-2 - (4 - fluoro - 3,5 - dimethylphenyl)-4 - methyl - 2H,4H,5H,6H,7H - pyrazolo[4,3 - c]pyridine - 5 - carbonyl]-1H - indol - 1 - yl}-3 - azabicyclo[3.1.0]hex - 6 - yl]-4,5 - dihydro - 1,2,4 - oxadiazol - 5 - one (C - 2)

[0904]

[0905] At 0 °C, acetyl chloride (1.9 mg, 0.024 mmol) was slowly added to a mixture of C - 1 (20.0 mg, 0.022 mmol) and triethylamine (4.5 mg, 0.044 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at 0 °C for 1 h, quenched with saturated ammonium chloride (3 mL), and extracted with dichloromethane (5 mL × 2). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to give C - 2 (10.0 mg, 48%), as a yellow solid.

[0906] ESI-MS (m / z): [M+H] + = 952.4。

[0907] 1 H NMR (400 MHz, DMSO-d 6)δ 11.76 (s, 1H), 8.32 (s, 1H), 7.65 (m, 2H), 7.49 (m, 2H), 7.24 (m, 3H), 7.09 (s, 1H), 6.96 (m, 2H), 5.68 (m, 1H), 4.29 (m, 1H), 4.09 (m, 3H), 3.71 (m, 3H), 3.45 - 3.32 (m, 7H), 3.05 (m, 2H), 2.95 - 2.61 (m, 2H), 2.24 (m, 6H), 2.00 (m, 1H), 1.83 (m, 2H), 1.75 - 1.61 (m, 2H), 1.46 (m, 3H), 1.27 (s, 3H), 1.18 (s, 3H).

[0908] Example 20: 3 - [(1R,5S,6S) - 6 - {5 - [(4S) - 2,2 - dimethyloxan - 4 - yl] - 2 - [(4S) - 3 - [3 - (4 - fluoro - 1 - methyl - 1H - indazol - 5 - yl) - 2 - oxo - 2,3 - dihydro - 1H - imidazol - 1 - yl] - 2 - (4 - fluoro - 3,5 - dimethylphenyl) - 4 - methyl - 2H,4H,5H,6H,7H - pyrazolo[4,3 - c]pyridine - 5 - carbonyl] - 1H - indol - 1 - yl} - 3 - (methylsulfonyl) - 3 - azabicyclo[3.1.0]hex - 6 - yl] - 4,5 - dihydro - 1,2,4 - oxadiazol - 5 - one (C - 3)

[0909] The title compound was obtained by a method similar to that of Example 19, replacing acetyl chloride with methanesulfonyl chloride.

[0910] ESI - MS (m / z): [M + H] + = 988.5.

[0911] Example 21: 3 - [(1R,5S,6S) - 3 - (cyclopropanesulfonyl) - 6 - {5 - [(4S) - 2,2 - dimethyloxan - 4 - yl] - 2 - [(4S) - 3 - [3 - (4 - fluoro - 1 - methyl - 1H - indazol - 5 - yl) - 2 - oxo - 2,3 - dihydro - 1H - imidazol - 1 - yl] - 2 - (4 - fluoro - 3,5 - dimethylphenyl) - 4 - methyl - 2H,4H,5H,6H,7H - pyrazolo[4,3 - c]pyridine - 5 - carbonyl] - 1H - indol - 1 - yl} - 3 - azabicyclo[3.1.0]hex - 6 - yl] -

[0912] 4,5 - dihydro - 1,2,4 - oxadiazol - 5 - one (C - 4)

[0913] The title compound was obtained by a method similar to that of Example 19, replacing acetyl chloride with cyclopropanesulfonyl chloride.

[0914] ESI-MS (m / z): [M+H] + = 1014.6

[0915] Example 22: (1R,5S,6S)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxamide (C-5)

[0916] The title compound was obtained by replacing acetyl chloride with phenyl carbamate in a similar manner to Example 19.

[0917] ESI-MS (m / z): [M+H] + = 953.4

[0918] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.55–7.42 (m, 2H), 7.35–7.12 (m, 4H), 7.11–7.06 (m, 1H), 6.97 (s, 1H), 5.83–5.60 (m, 2H), 4.15–4.03 (m, 4H), 3.86–3.66 (m, 3H), 3.53–3.39 (m, 2H), 3.03 (s, 2H), 2.88–2.63 (m, 3H), 2.27–2.24 (m, 6H), 1.72–1.64 (m, 2H), 1.62–1.48 (m, 3H), 1.47–1.40 (m, 3H), 1.31–1.22 (m, 5H), 1.19–1.15 (m, 3H).

[0919] Example 23: 3-[(1R,5S,6S)-3-Cyclopropanecarbonyl-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-6)

[0920] The title compound was obtained by replacing acetyl chloride with cyclopropanecarbonyl chloride in a similar manner to Example 19.

[0921] ESI-MS (m / z): [M+H] + = 978.4.

[0922] Example 24: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(1-fluorocyclopropanecarbonyl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-7)

[0923] A mixture of C-1 (20.0 mg, 0.022 mmol), 1-fluorocyclopropanecarboxylic acid (2.8 mg, 0.026 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.0 mg, 0.026 mmol), and 1-hydroxy-1H-benzotriazole in N,N-dimethylformamide (0.5 mL) was stirred at 25 °C for 2 h. The reaction mixture was purified by C-18 reverse-phase column chromatography (water / acetonitrile = 60 / 40 to 30 / 70) to give C-7 (9.2 mg, 42%) as a white solid.

[0924] ESI-MS (m / z): [M+H] + = 996.4.

[0925] 1 1H NMR (400 MHz, DMSO d 6)δ8.32(s,1H),7.65(d,J=8.9Hz,1H),7.55–7.44(m,2H),7.36–7.14(m,5H),7.10–7.06(m,1H),6.96(s,1H),5.72–5.60(m,1H),4.62–4.23(m,1H),4.12(s,4H),3.78–3.56(m,4H),3.22–2.97(m,2H),2.94–2.59(m,3H),2.28–2.18(m,6H),1.71–1.64(m,2H),1.64–1.48(m,3H),1.46–1.41(m,3H),1.30–1.21(m,9H),1.21–1.17(m,3H).

[0926] Example 25: 1-[(4S)-5-{1-[(1R,5S,6S)-3-acetyl-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxan-4-yl)-1H-indole-2-carbonyl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2,3-dihydro-1H-imidazol-2-one (C-8)

[0927] The title compound was obtained by replacing A-1 with A-3 in a similar manner to Examples 18 and 19.

[0928] ESI-MS (m / z): [M + H] + = 908.4.

[0929] 1 1H NMR (400 MHz, DMSO-d 6 )δ8.28(m,1H),7.91(m,1H),7.66(m,1H),7.58 - 7.46(m,1H),7.39(s,1H),7.22(m,4H),7.09(s,1H),6.97(s,1H),6.65(m,1H),4.61(m,1H),4.09(m,3H),3.96(m,3H),3.76(m,2H),3.44(m,3H),2.94 - 2.59(m,5H),2.23(m,6H),2.07 - 1.90(m,2H),1.73(m,4H),1.53(m,6H).

[0930] Example 26: 1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-[5-(oxan-4-yl)-1-[(1R,5S,6S)-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-1H-indole-2-carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro-1H-imidazol-2-one (C-9)

[0931] The title compound was obtained by replacing A-1 with A-3 in a similar manner to Example 18.

[0932] ESI-MS (m / z): [M+H] + = 910.4.

[0933] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.92 (s, 1H), 8.29 (m, 1H), 7.85 (s, 1H), 7.60 (m, 1H), 7.45 (m, 2H), 7.34 (s, 1H), 7.20 - 7.02 (m, 4H), 6.89 (m, 1H), 6.63 (m, 1H), 5.46 (m, 1H), 4.09 (m, 3H), 3.96 (m, 2H), 3.47 (m, 9H), 2.84 (m, 3H), 2.62 (m, 2H), 2.24 (s, 6H), 1.73 (s, 4H), 1.31 (m, 2H).

[0934] Example 27: 1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-{1-[(1R,5S,6S)-3-methyl-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-5-(oxan-4-yl)-1H-indole-2-carbonyl}-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro-1H-imidazol-2-one (C-10)

[0935]

[0936] A mixture of C-9 (20.0 mg, 0.023 mmol), aqueous formaldehyde solution (2.3 mg, 0.028 mmol) and acetic acid (2.8 mg, 0.046 mmol) in methanol (5 mL) was stirred at 25 °C for 30 min. Sodium borohydride (2.9 mg, 0.046 mmol) was added. The reaction mixture was stirred at 25 °C for 30 min, quenched with saturated ammonium chloride (3 mL), and extracted with dichloromethane (5 mL×2). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to give C-10 (10.0 mg, 48%) as a white solid.

[0937] ESI-MS (m / z): [M+H] + = 908.4.

[0938] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (m, 1H), 7.87 - 7.28 (m, 5H), 7.22 - 7.01 (m, 3H), 6.89 (m, 1H), 6.67 (m, 1H), 5.60 (m, 1H), 4.10 (m, 3H), 3.96 (m, 2H), 3.73 - 3.40 (m, 4H), 3.34 (m, 4H), 2.65 (m, 5H), 2.47 (m, 2H), 2.24 (s, 6H), 1.72 (s, 4H), 1.31 (m, 3H), 1.23 (s, 2H).

[0939] Example 28: (1R,5S,6R)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-{3-[4-fluoro-1-( 2 H 3 )methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3λ 6 -thiatricyclo[3.1.0]hexane-3,3-dione (C-11)

[0940]

[0941] A-4 (10.0 mg, 0.021 mmol), B-5 (10.1 mg, 0.021 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.7 mg, 0.025 mmol) and 1-hydroxybenzotriazole (4.2 mg, 0.030 mmol) in a mixture of N,N-dimethylformamide (0.2 mL) was stirred at 25 °C for 2 h. The reaction mixture was purified by C-18 reverse phase column chromatography (water / acetonitrile = 1 / 3) to give C-11 (12.3 mg, 62%) as a white solid.

[0942] ESI-MS (m / z): [M+H] + = 962.4.

[0943] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.59–7.40 (m, 2H), 7.30–7.12 (m, 4H), 7.08 (d, J = 3.1 Hz, 1H), 6.99–6.89 (m, 2H), 5.70–5.45 (m, 1H), 4.63–4.39 (m, 1H), 3.85–3.55 (m, 5H), 3.23–3.12 (m, 1H), 3.10–2.99 (m, 1H), 2.94–2.77 (m, 2H), 2.76–2.61 (m, 1H), 2.30–2.19 (m, 6H), 1.73–1.64 (m, 3H), 1.64–1.48 (m, 2H), 1.42–1.32 (m, 3H), 1.30–1.22 (m, 5H), 1.22–1.14 (m, 3H).

[0944] Example 29: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-12)

[0945]

[0946] Step A: (1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-azabicyclo[3.1.0]hexane-6-carbonitrile (C-12-1)

[0947] To a mixture of C-1-1 (500 mg, 0.53 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at 25 °C for 2 h and concentrated to dryness under reduced pressure. The residue was treated with water, quenched with saturated sodium bicarbonate solution, and extracted with dichloromethane (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give C-12-1 (400 mg) as a brown solid.

[0948] ESI-MS (m / z): [M+H] + = 850.9.

[0949] Step B: (1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (C-12-2)

[0950] Under a nitrogen atmosphere, a mixture of C-12-1 (350 mg, 0.41 mmol), 2-bromopyrimidine (97.77 mg, 0.61 mmol), copper(I) iodide (7.81 mg, 0.041 mmol), 2-(2,6-dimethylphenylamino)-2-oxoacetic acid (15.84 mg, 0.082 mmol) and potassium phosphate (174.06 mg, 0.82 mmol) in N,N-dimethylformamide (7 mL) was stirred at 90 °C for 16 h. The reaction mixture was cooled to 25 °C, quenched with water (5 mL), and extracted with dichloromethane (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 3) to give C-12-2 (250 mg, 65%) as a light yellow solid.

[0951] ESI-MS (m / z): [M+H] + = 929.1.

[0952] Step C: (1R,5S,6S)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-N'-hydroxy-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboximidamide (C-12-3)

[0953] To a mixture of C-12-2 (15 mg, 0.016 mmol) in ethanol (1 mL) was added sodium bicarbonate (14 mg, 0.16 mmol) and hydroxylamine hydrochloride (11 mg, 0.16 mmol). The reaction mixture was stirred at 70 °C for 6 h, cooled to 25 °C, quenched with water (1 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give C-12-3 (10 mg) as a yellow solid.

[0954] ESI-MS (m / z): [M+H] + = 962.3.

[0955] Step D: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-12)

[0956] To a mixture of C-12-3 (10 mg) in dimethyl sulfoxide (1 mL) was added N,N'-carbonyldiimidazole (5 mg, 0.032 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (6 mg, 0.040 mmol). The reaction mixture was stirred at 25 °C for 1 h, quenched with water (1 mL), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 5) to give C-12 (5 mg, 31%) as a white solid.

[0957] ESI-MS (m / z): [M+H] + = 989.0.

[0958] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.36 - 8.21 (m, 3H), 7.88 - 7.59 (m, 2H), 7.57 - 7.45 (m, 2H), 7.33 - 7.26 (m, 1H), 7.23 - 7.09 (m, 3H), 6.99 - 6.77 (m, 2H), 6.69 - 6.62 (m, 1H), 5.75 - 5.61 (m, 1H), 4.62 - 4.30 (m, 1H), 4.21 - 4.06 (m, 4H), 3.82 - 3.51 (m, 6H), 3.16 - 2.58 (m, 5H), 2.39 - 2.12 (m, 7H), 1.72 - 1.65 (m, 2H), 1.63 - 1.53 (m, 2H), 1.52 - 1.43 (m, 3H), 1.30 - 1.23 (m, 4H), 1.19 (s, 3H).

[0959] Example 30: 1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-[5-(oxan-4-yl)-1-[(1R,5S,6S)-3-(propan-2-yl)-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro-1H-imidazol-2-one (C-13)

[0960] The title compound was obtained by replacing aqueous formaldehyde solution with acetone according to a method similar to that of Example 27.

[0961] ESI-MS (m / z): [M+H] + = 908.4.

[0962] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (m, 1H), 7.62 (m, 2H), 7.40 (m, 3H), 7.12 (m, 4H), 6.94 (s, 1H), 6.71 (s, 1H), 5.62 (s, 1H), 4.10 (m, 4H), 3.96 (m, 2H), 3.48 (m, 4H), 2.81 (m, 4H), 2.25 (s, 6H), 1.73 (s, 4H), 1.22 (m, 14H).

[0963] Example 31: 1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-[5-(oxan-4-yl)-1-[(1R,5S,6S)-3-(oxetan-3-yl)-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro-1H-imidazol-2-one (C-14)

[0964] The title compound was obtained by replacing aqueous formaldehyde solution with 3-oxetanone according to a method similar to that of Example 27.

[0965] ESI-MS (m / z): [M+H] + = 922.4.

[0966] 1 H NMR (400 MHz, DMSO-d 6)δ8.33(s,1H),8.00(m,1H),7.66(m,1H),7.57 - 7.34(m,3H),7.29(s,1H),7.22 - 7.07(m,3H),6.98(s,1H),6.75(s,1H),5.74(s,1H),4.85(m,1H),4.56(m,1H),4.27(m,3H),4.12(s,3H),3.96(m,3H),3.44(m,4H),3.11(m,2H),2.84(s,2H),2.26(s,6H),1.72(s,4H),1.47(m,4H),1.23(s,3H).

[0967] Example 32: 1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-[5-(oxan-4-yl)-1-[(1R,5S,6S)-3-(oxolan-3-yl)-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro-1H-imidazol-2-one (C-15)

[0968] The title compound was obtained by replacing aqueous formaldehyde solution with dihydro-3(2H)-furanone according to a method similar to that of Example 27.

[0969] ESI-MS (m / z): [M + H] + = 936.4.

[0970] 1 1H NMR (400 MHz, DMSO-d 6 )δ15.32(s,1H),8.29(m,1H),7.94(s,1H),7.66(m,1H),7.54 - 7.44(m,1H),7.42(s,1H),7.27(s,1H),7.19(m,2H),7.10(s,1H),6.98(s,1H),6.73(s,1H),5.73(s,1H),4.10(m,5H),3.96(m,2H),3.56 - 3.40(m,6H),3.26(m,2H),3.22 - 2.97(m,2H),2.82(m,3H),2.67(m,2H),2.26(s,6H),1.72(s,5H),1.44(m,3H),1.23(s,2H).

[0971] Example 33: 1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-[5-(oxan-4-yl)-1-[(1R,5S,6S)-3-(oxan-4-yl)-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-1H-indole-2-carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro-1H-imidazol-2-one (C-16)

[0972] The title compound was obtained by replacing aqueous formaldehyde solution with tetrahydro-2H-pyran-4-one in a similar method to Example 27.

[0973] ESI-MS (m / z): [M+H] + = 949.9.

[0974] 1 H NMR (400 MHz, DMSO-d 6 ) δ 15.27 (m, 1H), 8.32 (s, 1H), 7.91 - 7.88 (m, 1H), 7.66 - 7.64 (m, 1H), 7.46 - 7.44 (m, 2H), 7.28 - 7.19 (m, 2H), 7.11 - 7.09 (m, 1H), 6.98 - 6.75 (m, 2H), 5.69 (s, 1H), 4.12 (m, 5H), 3.97 - 3.95 (m, 4H), 3.61 - 3.45 (m, 8H), 3.16 (m, 4H), 2.84 - 2.81 (m, 3H), 2.70 - 2.67 (m, 2H), 2.25 (m, 6H), 1.72 (m, 3H), 1.46 (m, 4H), 1.05 (m, 1H), 0.96 - 0.85 (m, 1H).

[0975] Example 34: 1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-[5-(oxan-4-yl)-1-[(1R,5S,6S)-3-[(1r,4S)-4-hydroxycyclohexyl]-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-1H-indole-2-carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro-1H-imidazol-2-one

[0976] and 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-[5-(oxan-4-yl)-1-[(1R,5S,6S)-3-[(1s,4R)-4-hydroxycyclohexyl]-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro-1H-imidazol-2-one (C-17 and C-18)

[0977] Two diastereomeric compounds were obtained by replacing aqueous formaldehyde solution with 4-hydroxycyclohexanone according to a method similar to Example 27, and arbitrarily designated as C-17 and C-18.

[0978] C-17:

[0979] ESI-MS (m / z): [M+H] + = 963.9.

[0980] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.35 - 8.22 (m, 1H), 7.64 - 7.31 (m, 4H), 7.23 - 7.03 (m, 4H), 7.00 - 6.84 (m, 1H), 6.78 - 6.63 (m, 1H), 5.65 - 5.44 (m, 1H), 4.44 - 4.30 (m, 1H), 4.14 - 4.06 (m, 5H), 4.00 - 3.93 (m, 2H), 3.76 - 3.66 (m, 1H), 3.55 - 3.43 (m, 4H), 3.07 - 2.93 (m, 1H), 2.87 - 2.64 (m, 4H), 2.24 (s, 6H), 2.03 - 1.94 (m, 1H), 1.73 (s, 5H), 1.61 - 1.49 (m, 3H), 1.46 - 1.35 (m, 4H), 1.30 - 1.19 (s, 6H).

[0981] C-18:

[0982] ESI-MS (m / z): [M+H] + = 963.9.

[0983] 1 H NMR (400 MHz, DMSO-d 6)δ8.35 - 8.22(m, 1H), 7.72 - 7.63(m, 1H), 7.50 - 7.27(m, 3H), 7.24 - 7.02(m, 4H), 6.99 - 6.86(m, 1H), 6.78 - 6.61(m, 1H), 5.69 - 5.37(m, 1H), 4.70 - 4.51(m, 1H), 4.16 - 4.04(m, 5H), 4.00 - 3.93(m, 2H), 3.54 - 3.37(m, 5H), 3.09 - 2.98(m, 1H), 2.90 - 2.78(m, 2H), 2.71 - 2.63(m, 1H), 2.25(s, 6H), 1.80 - 1.66(m, 6H), 1.43 - 1.00(m, 14H).

[0984] Example 35: 1 - [(4S)-5-{1-[(1R,5S,6S)-3-(4,4-difluorocyclohexyl)-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxan-4-yl)-1H-indole-2-carbonyl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2,3-dihydro-1H-imidazol-2-one (C-19)

[0985] The title compound was obtained by replacing aqueous formaldehyde solution with 4,4-difluorocyclohexanone according to a method similar to that of Example 27.

[0986] ESI-MS (m / z): [M + H] + = 984.8.

[0987] 1 1H NMR (400 MHz, DMSO-d 6)δ8.33(s,1H),7.99(d,J=8.4Hz,1H),7.66(d,J=8.8Hz,1H),7.51-7.45(m,1H),7.40(s,1H),7.25(s,1H),7.20(d,J=6.0Hz,2H),7.09(s,1H),6.98(s,1H),5.74(d,J=6.4Hz,1H),5.31-5.33(m,1H),4.12(s,5H),3.96(d,J=10.8Hz,2H),3.52-3.40(m,3H),2.99-2.72(m,2H),2.69-2.53(m,2H),2.45-2.39(m,1H),2.36-2.11(m,8H),2.05-1.86(m,4H),1.78-1.64(m,4H),1.57-1.11(m,10H).

[0988] Example 36: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-20)

[0989]

[0990] A mixture of C-1 (20.0 mg, 0.022 mmol), 2-bromo-5-methyl-1,3,4-oxadiazole (5.4 mg, 0.033 mmol) and potassium carbonate (6.1 mg, 0.044 mmol) in N,N-dimethylformamide (0.3 mL) was stirred at 90 °C for 12 h. The reaction mixture was cooled to 25 °C and purified by C-18 reverse-phase column chromatography (water / acetonitrile = 1 / 4) to give C-7 (10.3 mg, 47%) as a white solid.

[0991] ESI-MS (m / z): [M+H] + = 992.7.

[0992] 1 H NMR (400 MHz, DMSO d 6)δ8.33(s,1H),7.66(d,J=8.9Hz,1H),7.53–7.44(m,2H),7.33–7.25(m,1H),7.22–7.12(m,3H),7.10(d,J=3.1Hz,1H),6.97(s,1H),5.72–5.64(m,1H),4.18–4.06(m,4H),3.99–3.87(m,1H),3.83–3.64(m,5H),3.24–3.10(m,1H),3.08–

[0993] 2.98(m,1H),2.94–2.78(m,2H),2.75–2.59(m,1H),2.30(s,3H),2.26(s,6H),1.73–1.64(m,3H),1.63–1.49(m,2H),1.47–1.42(m,3H),1.30–1.22(m,5H),1.20–1.17(m,3H).

[0994] Example 37: 1-[(4S)-5-{1-[(1R,5S,6S)-3-cyclopropyl-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxan-4-yl)-1H-indole-2-carbonyl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2,3-dihydro-1H-imidazol-2-one (C-21)

[0995] The title compound was obtained in a similar manner to Example 27 by replacing the aqueous formaldehyde solution with 1-ethoxy-1-(trimethylsilyloxy)cyclopropane.

[0996] ESI-MS(m / z): [M+H] + = 905.9.

[0997] 1 H NMR(400MHz, DMSO-d 6)δ8.33(s,1H),7.97(d,J=8.4Hz,1H),7.66(d,J=8.8Hz,1H),7.48(s,1H),7.41(s,1H),7.29(s,1H),7.20(d,J=6.0Hz,2H),7.10(s,1H),6.98(s,1H),6.80 - 6.60(m,1H),5.74(s,1H),4.13(s,3H),3.96(d,J=10.8Hz,2H),3.52 - 3.40(m,3H),3.10(d,J=8.4Hz,1H),2.95 - 2.70(m,4H),2.37 - 2.13(m,8H),2.04 - 1.93(m,1H),1.76 - 1.66(m,5H),1.52 - 1.44(m,4H),1.37 - 1.10(m,6H).

[0998] Example 38: 3 - [(1R,5S,6S) - 6 - {5 - [(4S) - 2,2 - dimethyloxan - 4 - yl] - 2 - [(4S) - 3 - [3 - (4 - fluoro - 1 - methyl - 1H - indazol - 5 - yl) - 2 - oxo - 2,3 - dihydro - 1H - imidazol - 1 - yl] - 2 - (4 - fluoro - 3,5 - dimethylphenyl) - 4 - methyl - 2H,4H,5H,6H,7H - pyrazolo[4,3 - c]pyridine - 5 - carbonyl] - 1H - indol - 1 - yl} - 3 - (pyridin - 2 - yl) - 3 - azabicyclo[3.1.0]hex - 6 - yl] - 4,5 - dihydro - 1,2,4 - oxadiazol - 5 - one (C - 22)

[0999] The title compound was obtained by a method similar to Example 29 using 2 - bromopyridine in place of 2 - bromopyrimidine.

[1000] ESI - MS(m / z): [M + H] + = 986.9.

[1001] 1 H NMR(400MHz,DMSO - d 6)δ8.33(s,1H),8.00(s,1H),7.82 - 7.68(m,1H),7.66(d,J=8.8Hz,1H),7.54 - 7.36(m,2H),7.32 - 7.15(m,2H),7.14 - 7.06(m,2H),6.98(s,1H),6.70 - 6.26(m,4H),5.69(d,J=6.4Hz,1H),4.12(s,3H),3.72(d,J=7.2Hz,2H),3.64 - 3.48(m,4H),3.10 - 2.95(m,2H),2.92 - 2.62(m,2H),2.35 - 2.15(m,7H),2.00(dd,J=14.4,7.2Hz,1H),1.76 - 1.39(m,6H),1.28(s,3H),1.23(s,3H),1.19(s,3H).

[1002] Example 39: 3 - [(1R,5S,6S)-6-{5-[(4S)-2,2 - dimethyloxan - 4 - yl]-2-[(4S)-3-[3-(4 - fluoro - 1 - methyl - 1H - indazol - 5 - yl)-2 - oxo - 2,3 - dihydro - 1H - imidazol - 1 - yl]-2-(4 - fluoro - 3,5 - dimethylphenyl)-4 - methyl - 2H,4H,5H,6H,7H - pyrazolo[4,3 - c]pyridine - 5 - carbonyl]-1H - indol - 1 - yl}-3-(pyrimidin - 5 - yl)-3 - azabicyclo[3.1.0]hex - 6 - yl]-4,5 - dihydro - 1,2,4 - oxadiazol - 5 - one (C - 23)

[1003] The title compound was obtained by replacing 2 - bromopyrimidine with 5 - bromopyrimidine according to a method similar to that of Example 29.

[1004] ESI - MS(m / z): [M + H] + = 988.8.

[1005] 1 H NMR(400MHz,DMSO - d 6)δ8.42(s,1H),8.33(s,1H),8.18 - 7.90(m,2H),7.80 - 7.60(m,2H),7.55 - 7.35(m,2H),7.33 - 7.05(m,3H),6.98(s,1H),6.65(s,1H),5.70(d,J=6.0Hz,1H),5.32(t,J=4.8Hz,1H),4.29 - 3.90(m,5H),3.78 - 3.66(m,2H),3.60 - 3.45(m,2H),3.08 - 2.96(m,2H),2.53(d,J=5.6Hz,1H),2.22 - 2.16(m,1H),2.26(s,6H),2.04 - 1.94(m,2H),1.75 - 1.40(m,6H),1.28(s,3H),1.23(s,3H),1.19(s,3H).

[1006] Example 40: 3 - [(1R,5S,6S) - 6 - {5 - [(4S) - 2,2 - dimethyloxan - 4 - yl] - 2 - [(4S) - 3 - [3 - (4 - fluoro - 1 - methyl - 1H - indazol - 5 - yl) - 2 - oxo - 2,3 - dihydro - 1H - imidazol - 1 - yl] - 2 - (4 - fluoro - 3,5 - dimethylphenyl) - 4 - methyl - 2H,4H,5H,6H,7H - pyrazolo[4,3 - c]pyridine - 5 - carbonyl] - 1H - indol - 1 - yl} - 3 - (pyridazin - 3 - yl) - 3 - azabicyclo[3.1.0]hex - 6 - yl] - 4,5 - dihydro - 1,2,4 - oxadiazol - 5 - one (C - 24)

[1007] The title compound was obtained by a method similar to Example 29, replacing 2 - bromopyrimidine with 3 - chloropyridazine.

[1008] ESI - MS(m / z): [M + H] + = 988.3.

[1009] 1 H NMR(400MHz,DMSO - d 6 )δ8.52(s,1H),8.33(s,1H),7.67 - 7.65(m,2H),7.52 - 7.48(m,2H),7.33(m,3H),7.21 - 7.19(m,2H),7.10(m,1H),6.99 - 6.92(m,2H),5.70(s,1H),4.35(m,1H),4.12(s,3H),3.74 - 3.71(m,6H),3.05 - 2.89(m,4H),2.33 - 2.21(m,7H),1.69 - 1.50(m,7H),1.28 - 1.19(m,8H).

[1010] Example 41: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyrazin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-25)

[1011] The title compound was obtained by replacing 2-bromopyrimidine with 2-bromopyrazine in a similar manner to Example 29.

[1012] ESI-MS (m / z): [M+H] + = 988.5.

[1013] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 8.05 - 7.95 (m, 2H), 7.82 (s, 1H), 7.74 - 7.60 (m, 2H), 7.55 - 7.46 (m, 2H), 7.35 - 7.28 (m, 1H), 7.23 - 7.16 (m, 2H), 7.12 - 7.08 (m, 1H), 7.02 - 6.84 (m, 2H), 5.83 - 5.62 (m, 1H), 4.38 - 4.31 (m, 1H), 4.19 - 4.07 (s, 3H), 3.76 - 3.60 (m, 6H), 3.21 - 3.01 (m, 2H), 2.88 - 2.64 (m, 2H), 2.29 - 2.21 (m, 7H), 1.69 - 1.49 (m, 7H), 1.28 (s, 3H), 1.23 (s, 2H), 1.19 (s, 3H).

[1014] Example 42: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(1-methyl-1H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-26)

[1015] The title compound was obtained by replacing 2-bromopyrimidine with 3-bromo-1-methyl-1,2,4-triazole according to a method similar to that of Example 29.

[1016] ESI-MS (m / z): [M+H] + = 991.7.

[1017] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.32 (m, 1H), 7.99 (m, 1H), 7.67 - 7.64 (m, 2H), 7.49 (s, 2H), 7.29 - 7.10 (m, 5H), 6.97 - 6.88 (m, 1H), 5.69 (m, 1H), 4.12 (s, 3H), 3.73 - 3.71 (m, 2H), 3.64 (s, 3H), 3.51 - 3.46 (m, 2H), 3.12 - 2.98 (m, 2H), 2.93 - 2.66 (m, 2H), 2.26 - 2.21 (m, 7H), 2.02 - 1.98 (m, 1H), 1.69 - 1.46 (m, 9H), 1.28 (s, 3H), 1.25 - 1.23 (m, 2H), 1.18 (s, 3H).

[1018] Example 43: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-27)

[1019] The title compound was obtained by substituting 2-bromopyrimidine with 5-bromo-2-methyl-2H-tetrazole in a similar manner to Example 29.

[1020] ESI-MS (m / z): [M+H] + = 992.6.

[1021] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.56 - 7.44 (m, 2H), 7.29 (s, 1H), 7.19 (d, J = 6.0 Hz, 2H), 7.09 (s, 1H), 6.97 (s, 1H), 6.90 (s, 1H), 5.69 (d, J = 5.6 Hz, 1H), 4.12 (s, 6H), 3.73 - 3.52 (m, 4H), 3.13 - 2.93 (m, 2H), 2.90 - 2.78 (m, 2H), 2.26 (s, 6H), 2.24 - 2.15 (m, 1H), 2.04 - 1.94 (m, 1H), 1.74 - 1.36 (m, 9H), 1.28 (s, 3H), 1.27 - 1.21 (m, 2H), 1.19 (s, 3H).

[1022] Example 44: 3-[(1R,5S,6S)-6-{2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-(oxan-4-yl)-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-28)

[1023] The title compound was obtained by substituting A-1 with A-2 in a similar manner to Examples 18 and 29.

[1024] ESI-MS (m / z): [M+H] + = 961.3.

[1025] 1 H NMR (400 MHz, DMSO-d 6)δ 8.38 (d, J = 20.0 Hz, 3H), 8.27 (s, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.22 (d, J = 6.8 Hz, 2H), 7.06 (d, J = 40.4 Hz, 1H), 6.69 (s, 1H), 6.55 (d, J = 5.6 Hz, 1H), 5.35 (s, 1H), 4.15 (s, 3H), 4.00 (d, J = 10.4 Hz, 2H), 3.80 - 3.71 (m, 3H), 3.69 - 3.61 (m, 2H), 2.93 - 2.80 (m, 2H), 2.28 (s, 3H), 2.25 - 2.13 (m, 2H), 2.03 (d, J = 8.0 Hz, 2H), 1.82 - 1.68 (m, 2H), 1.54 - 1.39 (m, 3H), 1.26 (s, 6H), 0.87 (d, J = 6.8 Hz, 2H).

[1026] Example 45: 3 - [(1R,5S,6S) - 6 - {5 - [(4S) - 2,2 - dimethyloxan - 4 - yl] - 2 - [(4S) - 3 - {3 - [4 - fluoro - 1 - ( 2 H 3 )methyl - 1H - indazol - 5 - yl] - 2 - oxo - 2,3 - dihydro - 1H - imidazol - 1 - yl} - 2 - (4 - fluoro - 3,5 - dimethylphenyl) - 4 - methyl - 2H,4H,5H,6H,7H - pyrazolo[4,3 - c]pyridine - 5 - carbonyl] - 1H - indol - 1 - yl} - 3 - (pyrimidin - 2 - yl) - 3 - azabicyclo[3.1.0]hex - 6 - yl] - 4,5 - dihydro - 1,2,4 - oxadiazol - 5 - one (C - 29)

[1027] The title compound was obtained by replacing B - 1 with B - 5 in a similar manner to Examples 18 and 29.

[1028] ESI - MS (m / z): [M + H] + = 991.5.

[1029] 1 H NMR (400 MHz, DMSO - d 6)δ8.36 - 8.21(m, 3H), 7.88 - 7.59(m, 2H), 7.57 - 7.45(m, 2H), 7.33 - 7.26(m, 1H), 7.23 - 7.09(m, 3H), 6.99 - 6.77(m, 2H), 6.69 - 6.62(m, 1H), 5.75 - 5.61(m, 1H), 4.21 - 4.06(m, 1H), 3.82 - 3.51(m, 6H), 3.16 - 2.58(m, 5H), 2.39 - 2.12(m, 7H), 1.72 - 1.65(m, 2H), 1.63 - 1.53(m, 2H), 1.52 - 1.43(m, 3H), 1.30 - 1.23(m, 4H), 1.19(s, 3H).

[1030] Example 46: 3 - [(1R,5S,6S)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyridin-3-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-30)

[1031] The title compound was obtained by a method similar to Example 29, replacing 2-bromopyrimidine with 3-bromopyridine.

[1032] ESI-MS (m / z): [M + H] + = 987.4.

[1033] 1 H NMR (400 MHz, DMSO-d 6)δ8.31(s,1H),7.95 - 7.89(m,2H),7.68 - 7.65(m,2H),7.51 - 7.48(m,2H),7.36 - 7.27(m,1H),7.23 - 7.17(m,2H),7.16 - 7.08(m,2H),7.03 - 6.84(m,2H),5.72(s,1H),5.33 - 5.31(m,1H),4.12 - 4.07(m,5H),3.72(m,2H),3.52 - 3.41(m,1H),3.05(s,2H),2.84(s,2H),2.29 - 2.19(m,7H),2.00(m,2H),1.67(s,2H),1.59 - 1.44(m,7H),1.28(s,3H),1.19(s,3H).

[1034] Example 47: 3 - [(1R,5S,6S)-6-{5-[(4S)-2,2 - dimethyloxan - 4 - yl]-2-[(4S)-3-[3-(4 - fluoro - 1 - methyl - 1H - indazol - 5 - yl)-2 - oxo - 2,3 - dihydro - 1H - imidazol - 1 - yl]-2-(4 - fluoro - 3,5 - dimethylphenyl)-4 - methyl - 2H,4H,5H,6H,7H - pyrazolo[4,3 - c]pyridine - 5 - carbonyl]-1H - indol - 1 - yl}-3-(pyridazin - 4 - yl)-3 - azabicyclo[3.1.0]hex - 6 - yl]-4,5 - dihydro - 1,2,4 - oxadiazol - 5 - one (C - 31)

[1035] The title compound was obtained by a method similar to Example 29, replacing 2 - bromopyrimidine with 4 - bromopyridazine.

[1036] ESI - MS(m / z): [M + H] + = 988.5.

[1037] 1 1H NMR(400MHz, DMSO - d 6 )δ11.57(s,1H),8.31(m,1H),7.91(m,1H),7.66(m,2H),7.49(m,2H),7.30(m,1H),7.20(m,2H),7.12(m,3H),7.05 - 6.87(m,3H),5.32(m,1H),4.17 - 4.04(m,5H),3.72(m,2H),3.05(s,2H),2.84(s,2H),2.29 - 2.19(m,7H),2.00(m,2H),1.67(s,2H),1.59 - 1.44(m,6H),1.28(s,4H),1.19(s,3H).

[1038] Example 48: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-32)

[1039]

[1040] Step A: (1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-carbonitrile (C-32-1)

[1041] Under a nitrogen atmosphere, a mixture of C-12-1 (50.0 mg, 0.058 mmol), 4-chloropyrimidine hydrochloride (13.3 mg, 0.088 mmol) and diisopropylethylamine (22.8 mg, 0.018 mmol) in N,N-dimethylformamide (5 mL) was stirred at 120 °C for 16 h. The reaction mixture was cooled to 25 °C, quenched with water (5 mL), and extracted with ethyl acetate (10 mL × 2). The combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to give C-32-1 (30.0 mg, 55%) as a white solid.

[1042] ESI-MS (m / z): [M+H] + = 929.4.

[1043] Steps B and C were carried out in a similar manner to Example 29 to give the title compound.

[1044] ESI-MS (m / z): [M+H] + = 988.4.

[1045] 11H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s, 1H), 8.28 (m, 1H), 8.14 (s, 1H), 7.66 (m, 2H), 7.50 (m, 2H), 7.25 (m, 3H), 7.12 (m, 1H), 7.00 (m, 1H), 6.53 (s, 1H), 5.69 (m, 1H), 5.32 (m, 1H), 4.10 (s, 3H), 3.72 (m, 6H), 3.03 (m, 2H), 2.86 (s, 2H), 2.67 (s, 2H), 2.23 (m, 5H), 1.99 (m, 1H), 1.75 - 1.41 (m, 7H), 1.29 (s, 3H), 1.26 - 1.21 (m, 2H), 1.19 (s, 3H).

[1046] Example 49: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(5-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-33)

[1047] The title compound was obtained by replacing 2-bromopyrimidine with 2-bromo-5-methylpyrimidine according to a method similar to that of Example 29.

[1048] ESI-MS (m / z): [M / 2 + H] + = 502.5.

[1049] 1 1H NMR (400 MHz, DMSO-d 6)δ8.31(s,2H),7.88 - 7.59(m,2H),7.57 - 7.45(m,2H),7.33 - 7.26(m,1H),7.23 - 7.09(m,3H),6.99 - 6.77(m,2H),6.69 - 6.62(m,1H),5.75 - 5.61(m,1H),4.62 - 4.30(m,1H),4.21 - 4.06(m,4H),3.82 - 3.51(m,6H),3.16 - 2.58(m,5H),2.39 - 2.12(m,7H),1.72 - 1.65(m,2H),1.63 - 1.53(m,2H),1.52 - 1.43(m,3H),1.30 - 1.23(m,6H),1.19(s,3H).

[1050] Example 50: 3 - [(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(5-fluoropyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-34)

[1051] The title compound was obtained by a method similar to Example 29, replacing 2-bromopyrimidine with 2-bromo-5-fluoropyrimidine.

[1052] ESI-MS(m / z): [M + H] + = 1006.6.

[1053] 1 H NMR(400MHz, DMSO-d 6)δ8.43(s,2H),8.33(s,1H),8.07(s,1H),7.66(d,J=8.8Hz,1H),7.51-7.49(m,2H),7.35-7.24(m,1H),7.19(d,J=5.6Hz,2H),7.15-7.09(m,1H),7.01-6.90(m,1H),5.76-5.63(m,1H),5.36-5.30(m,1H),4.66(s,1H),4.12(s,3H),3.81-3.60(m,6H),3.10-2.96(m,2H),2.95-2.78(m,2H),2.37-2.13(m,7H),1.73-1.38(m,7H),1.28(s,3H),1.26-1.22(m,2H),1.19(s,3H).

[1054] Example 51: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-[5-(trifluoromethyl)pyrimidin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-35)

[1055] The title compound was obtained by replacing 4-chloropyrimidine hydrochloride with 2-chloro-5-(trifluoromethyl)pyrimidine according to a method similar to that of Example 48.

[1056] ESI-MS(m / z): [M+H] + = 1056.9.

[1057] 1 H NMR(400MHz,DMSO-d 6)δ 8.47 (s, 2H), 8.35 (s, 1H), 8.08 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.51 - 7.49 (m, 2H), 7.35 - 7.24 (m, 1H), 7.19 (d, J = 5.6 Hz, 2H), 7.15 - 7.09 (m, 1H), 7.01 - 6.90 (m, 1H), 5.76 - 5.63 (m, 1H), 5.36 - 5.30 (m, 1H), 4.66 (s, 1H), 4.12 (s, 3H), 3.81 - 3.60 (m, 6H), 3.10 - 2.96 (m, 2H), 2.95 - 2.78 (m, 2H), 2.37 - 2.13 (m, 7H), 1.73 - 1.38 (m, 7H), 1.28 (s, 3H), 1.26 - 1.22 (m, 2H), 1.19 (s, 3H).

[1058] Example 52: 3 - [(1R,5S,6S) - 6 - {5 - [(4S) - 2,2 - dimethyloxan - 4 - yl] - 2 - [(4S) - 3 - [3 - (4 - fluoro - 1 - methyl - 1H - indazol - 5 - yl) - 2 - oxo - 2,3 - dihydro - 1H - imidazol - 1 - yl] - 2 - (4 - fluoro - 3,5 - dimethylphenyl) - 4 - methyl - 2H,4H,5H,6H,7H - pyrazolo[4,3 - c]pyridine - 5 - carbonyl] - 1H - indol - 1 - yl} - 3 - (6 - methylpyridin - 2 - yl) - 3 - azabicyclo[3.1.0]hex - 6 - yl] - 4,5 - dihydro - 1,2,4 - oxadiazol - 5 - one (C - 36)

[1059] The title compound was obtained by using 2 - methyl - 6 - chloropyridine to replace 2 - bromopyrimidine according to a method similar to that of Example 29.

[1060] ESI - MS (m / z): [M - H] - = 998.9.

[1061] 1 H NMR (400 MHz, DMSO - d 6)δ8.32(s,1H),7.86 - 7.61(m,2H),7.55 - 7.38(m,2H),7.36 - 7.15(m,3H),7.14 - 7.06(m,2H),6.98(s,1H),6.43(s,1H),6.30 - 6.06(m,1H),5.74 - 5.65(m,1H),5.32(t,J=4.8Hz,1H),4.12(s,3H),4.06(d,J=5.6Hz,1H),3.72(d,J=7.2Hz,2H),3.62 - 3.46(m,2H),3.08 - 2.98(m,2H),2.92 - 2.60(m,2H),2.34 - 2.16(m,7H),2.04 - 1.94(m,2H),1.74 - 1.38(m,7H),1.28(s,3H),1.26 - 1.21(m,5H),1.19(s,3H).

[1062] Example 53: 3 - [(1R,5S,6S) - 6 - {5 - [(4S) - 2,2 - dimethyloxan - 4 - yl] - 2 - [(4S) - 3 - {3 - [4 - fluoro - 1 - (2,2,2 - trifluoroethyl) - 1H - indazol - 5 - yl] - 2 - oxo - 2,3 - dihydro - 1H - imidazol - 1 - yl} - 2 - (4 - fluoro - 3,5 - dimethylphenyl) - 4 - methyl - 2H,4H,5H,6H,7H - pyrazolo[4,3 - c]pyridine - 5 - carbonyl] - 1H - indol - 1 - yl} - 3 - (pyrimidin - 2 - yl) - 3 - azabicyclo[3.1.0]hex - 6 - yl] - 4,5 - dihydro - 1,2,4 - oxadiazol - 5 - one (C - 37)

[1063] The title compound was obtained by replacing B - 1 with B - 12 in a similar manner to Example 45.

[1064] ESI - MS(m / z): [M + H] + = 1056.5.

[1065] 1 H NMR(400MHz,DMSO - d 6)δ8.52(s,1H),8.32(d,J=4.4Hz,2H),7.83(d,J=8.8Hz,1H),7.75-7.56(m,1H),7.51(s,1H),7.30(s,1H),7.19(d,J=6.0Hz,1H),7.13(d,J=2.4Hz,1H),6.98(s,1H),6.94-6.75(m,1H),6.66(s,1H),5.69(s,1H),5.64-5.50(m,2H),4.53-4.05(m,3H),3.79-3.58(m,5H),3.20-2.98(m,2H),2.94-2.75(m,2H),2.68-2.57(m,1H),2.26(s,6H),2.23-2.16(m,1H),1.74-1.37(m,7H),1.28(s,3H),1.27-1.21(m,2H),1.19(s,3H).

[1066] Example 54: 3-[(1R,5S,6S)-3-(5-chloropyrimidin-2-yl)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-38)

[1067] The title compound was obtained by the method similar to Example 29 using 2-bromo-5-chloropyrimidine in place of 2-bromopyrimidine.

[1068] ESI-MS(m / z): [M+H] + = 1020.7.

[1069] 1 H NMR(400MHz,DMSO-d 6)δ8.41(s,2H),8.32(s,1H),7.66(d,J=8.8Hz,1H),7.50(s,2H),7.29(s,1H),7.19(d,J=6.0Hz,2H),7.10(s,1H),6.97(s,1H),6.94 - 6.85(m,1H),5.69(s,1H),5.33 - 5.31(m,1H),4.51 - 4.23(m,1H),4.12(s,3H),3.72(d,J=8.0Hz,4H),3.05(s,2H),2.85(s,2H),2.67(s,1H),2.35 - 2.17(m,8H),1.71 - 1.37(m,7H),1.46(s,3H),1.28(s,2H),1.19(s,3H).

[1070] Example 55: 1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-5-[5-(oxan-4-yl)-1-[(1R,5S,6S)-3-(pyrimidin-2-yl)-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carbonyl]-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydro-1H-imidazol-2-one (C-39)

[1071]

[1072] Under a nitrogen atmosphere, a mixture of C-9 (15.0 mg, 0.02 mmol), 2-bromopyrimidine (2.9 mg, 0.02 mmol), copper(I) iodide (0.3 mg, 0.002 mmol), (2,6-dimethoxyphenyl)amino](oxy)acetic acid (0.58 mg, 0.003 mmol) and potassium phosphate (6.4 mg, 0.03 mmol) in N,N-dimethylformamide (1 mL) was stirred at 90 °C for 4 h. The reaction mixture was cooled to 25 °C, quenched with water (1 mL), and extracted with dichloromethane (5 mL × 3). The combined organic layers were washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 5) to give C-39 (10.0 mg, 62%) as a white solid.

[1073] ESI-MS (m / z): [M + H] + = 944.8.

[1074] 11H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (s, 1H), 8.19 (s, 2H), 7.94 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.50 (s, 2H), 7.23 - 7.08 (m, 4H), 6.99 (s, 1H), 6.54 (s, 1H), 5.71 - 5.46 (m, 2H), 4.17 - 4.03 (m, 4H), 3.97 (d, J = 10.4 Hz, 4H), 3.66 (s, 2H), 3.46 (s, 2H), 3.17 (d, J = 5.2 Hz, 1H), 2.85 (s, 2H), 2.28 - 2.19 (s, 8H), 1.91 (s, 4H), 1.52 (d, J = 5.6 Hz, 2H), 1.24 (s, 3H).

[1075] Example 56: 3 - [(1R,5S,6S)-6-{2-[(4S)-2-(3-chloro-4-fluoro-5-methylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-40)

[1076] The title compound was obtained by replacing B-1 with B-2 in a similar manner to Example 45.

[1077] ESI-MS (m / z): [M+H] + = 1008.6.

[1078] 11H NMR (400 MHz, DMSO-d6) δ 8.35–8.27 (m, 3H), 7.66 (d, J = 8.9 Hz, 1H), 7.56–7.49 (m, 2H), 7.46–7.39 (m, 1H), 7.37–7.27 (m, 2H), 7.23–7.19 (m, 1H), 7.17 (d, J = 3.1 Hz, 1H), 7.12–7.03 (m, 1H), 6.69–6.58 (m, 1H), 5.76–5.66 (m, 1H), 4.52–4.28 (m, 1H), 4.17–4.02 (m, 4H), 3.76–3.59 (m, 5H), 3.25–3.13 (m, 1H), 3.08–2.98 (m, 1H), 2.94–2.77 (m, 2H), 2.74–2.60 (m, 1H), 2.44–2.35 (m, 3H), 1.73–1.65 (m, 3H), 1.63–1.50 (m, 2H), 1.48–1.42 (m, 3H), 1.30–1.21 (m, 5H), 1.20–1.16 (m, 3H).

[1079] Example 57: 3-[(1R,5S,6S)-6-{2-[(4S)-2-(3-chloro-4-fluoro-5-methylphenyl)-3-{3-[4-fluoro-1-( 2 H 3 )methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-41)

[1080] The title compound was obtained by replacing B-1 with B-6 in a similar manner to Example 45.

[1081] ESI-MS (m / z): [M+H] + = 1008.6.

[1082] 11H NMR (400 MHz, DMSO-d6) δ 8.35–8.27 (m, 3H), 7.66 (d, J = 8.9 Hz, 1H), 7.56–7.49 (m, 2H), 7.46–7.39 (m, 1H), 7.37–7.27 (m, 2H), 7.23–7.19 (m, 1H), 7.17 (d, J = 3.1 Hz, 1H), 7.12–7.03 (m, 1H), 6.69–6.58 (m, 1H), 5.76–5.66 (m, 1H), 4.52–4.28 (m, 1H), 4.17–4.02 (m, 4H), 3.76–3.59 (m, 5H), 3.25–3.13 (m, 1H), 3.08–2.98 (m, 1H), 2.94–2.77 (m, 2H), 2.74–2.60 (m, 1H), 2.44–2.35 (m, 3H), 1.73–1.65 (m, 3H), 1.63–1.50 (m, 2H), 1.48–1.42 (m, 3H), 1.30–1.21 (m, 5H), 1.20–1.16 (m, 3H).

[1083] Example 58: 3-[(1R,5S,6S)-6-{2-[(4S)-2-(3-chloro-4-fluorophenyl)-3-{3-[4-fluoro-1-( 2 H 3 )methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-42)

[1084] The title compound was obtained by replacing B-1 with B-11 in a similar manner to Example 45.

[1085] ESI-MS (m / z): [M+H] + = 997.5.

[1086] 1 1H NMR (400 MHz, DMSO d 6)δ 8.34–8.22 (m, 3H), 7.68–7.58 (m, 3H), 7.53–7.46 (m, 2H), 7.44–7.38 (m, 1H), 7.33–7.23 (m, 1H), 7.17–7.12 (m, 1H), 7.10–7.04 (m, 1H), 6.69–6.56 (m, 1H), 5.74–5.65 (m, 1H), 4.50–4.25 (m, 1H), 4.22–3.99 (m, 1H), 3.78–3.56 (m, 5H), 3.25–3.12 (m, 1H), 3.10–2.96 (m, 2H), 2.91–2.73 (m, 2H), 2.74–2.60 (m, 1H), 1.74–1.65 (m, 2H), 1.64–1.49 (m, 3H), 1.49–1.41 (m, 3H), 1.33–1.21 (m, 5H), 1.21–1.14 (m, 3H).

[1087] Example 59: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-{3-[4-fluoro-1-( 2 H 3 )methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-[4-fluoro-3-methyl-5-(trifluoromethyl)phenyl]-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-43)

[1088] The title compound was obtained by replacing B-1 with B-9 in a similar manner to Example 45.

[1089] ESI-MS (m / z): [M+H] + = 1145.5.

[1090] 1 H NMR (400 MHz, DMSO d 6)δ8.35–8.27(m,3H),7.81–7.76(m,1H),7.66(d,J=8.8Hz,1H),7.59–7.39(m,4H),7.35–7.25(m,1H),7.18(d,J=3.1Hz,1H),7.10(s,1H),6.69–6.61(m,1H),5.72(d,J=7.0Hz,1H),4.52–4.28(m,1H),4.23–4.09(m,1H),3.76–3.58(m,5H),3.26–3.11(m,1H),3.09–2.99(m,1H),2.95–2.75(m,2H),2.73–2.58(m,1H),2.42–2.31(m,4H),1.72–1.65(m,2H),1.64–1.50(m,2H),1.50–1.43(m,3H),1.29–1.22(m,5H),1.19(s,3H).

[1091] Example 60: 3-[(1R,5S,6S)-6-{2-[(4S)-2-(3,4-difluoro-5-methylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-44)

[1092] The title compound was obtained by replacing B-1 with B-4 in a similar manner to Example 45.

[1093] ESI-MS(m / z): [M+H] + = 992.4.

[1094] 1 H NMR(400MHz,DMSO d 6)δ8.36–8.26(m,3H),7.66(d,J=8.9Hz,1H),7.55–7.47(m,2H),7.37–7.18(m,4H),7.15(d,J=3.1Hz,1H),7.06(s,1H),6.65(s,1H),5.73–5.64(m,1H),4.54–4.28(m,1H),4.21–4.05(m,4H),3.75–3.58(m,5H),3.26–3.12(m,1H),3.10–2.99(m,1H),2.96–2.75(m,2H),2.73–2.58(m,1H),2.36–2.26(m,4H),1.74–1.64(m,2H),1.63–1.51(m,2H),1.51–1.42(m,3H),1.31–1.21(m,5H),1.21–1.16(m,3H).

[1095] Example 61: 5-[(4S)-5-{5-[(4S)-2,2-Dimethyloxan-4-yl]-1-[(1R,5S,6S)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carbonyl}-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl]-2-fluoro-3-methylbenzonitrile (C-45)

[1096] The title compound was obtained by replacing B-1 with B-3 in a similar manner to Example 45.

[1097] ESI-MS(m / z): [M+H] + = 999.6.

[1098] 1 H NMR(400MHz,DMSO d 6)δ8.35–8.27(m,3H),7.82–7.71(m,2H),7.68–7.63(m,1H),7.55–7.39(m,2H),7.35–7.25(m,1H),7.22–7.15(m,2H),7.08(s,1H),6.70–6.58(m,1H),5.73(s,1H),4.52–4.27(m,1H),4.19–4.05(m,4H),3.77–3.58(m,5H),3.25–3.12(m,1H),3.10–2.98(m,1H),2.95–2.77(m,2H),2.76–2.62(m,1H),2.40–2.29(m,3H),1.75–1.64(m,2H),1.66–1.52(m,3H),1.52–1.43(m,3H),1.31–1.22(m,5H),1.20–1.16(m,3H).

[1099] Example 62: 3-[(1R,5S,6S)-6-{2-[(4S)-2-(3,4-difluoro-5-methylphenyl)-3-{3-[4-fluoro-1-( 2 H 3 )methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-46)

[1100] The title compound was obtained by replacing B-1 with B-8 in a similar manner to Example 45.

[1101] ESI-MS (m / z): [M+H] + = 999.5.

[1102] 1 H NMR (400 MHz, DMSO d 6)δ 8.39–8.26 (m, 3H), 7.66 (d, J = 8.8 Hz, 1H), 7.56–7.45 (m, 2H), 7.39–7.18 (m, 3H), 7.15 (d, J = 3.1 Hz, 1H), 7.06 (s, 1H), 6.72–6.54 (m, 2H), 5.76–5.66 (m, 1H), 4.52–4.27 (m, 1H), 4.21–4.02 (m, 1H), 3.79–3.58 (m, 5H), 3.26–3.12 (m, 1H), 3.10–2.98 (m, 1H), 2.96–2.74 (m, 2H), 2.72–2.59 (m, 1H), 2.37–2.26 (m, 3H), 1.73–1.64 (m, 2H), 1.64–1.49 (m, 3H), 1.50–1.41 (m, 3H), 1.32–1.21 (m, 5H), 1.21–1.15 (m, 3H).

[1103] Example 63: 5-[(4S)-5-{5-[(4S)-2,2-Dimethyloxan-4-yl]-1-[(1R,5S,6S)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carbonyl}-3-{3-[4-fluoro-1-( 2 H 3 )methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl]-2-fluoro-3-methylbenzonitrile (C-47)

[1104] The title compound was obtained by replacing B-1 with B-7 in a similar manner to Example 45.

[1105] ESI-MS (m / z): [M + H] + = 1002.6.

[1106] 1 1H NMR (400 MHz, DMSO d 6)δ 8.38–8.25 (m, 3H), 7.72–7.61 (m, 2H), 7.58–7.38 (m, 2H), 7.36–7.15 (m, 3H), 7.13–7.05 (m, 1H), 6.68–6.52 (m, 2H), 5.75–5.68 (m, 1H), 4.54–4.26 (m, 1H), 4.23–3.98 (m, 1H), 3.79–3.57 (m, 5H), 3.24–3.14 (m, 1H), 3.07–2.99 (m, 1H), 2.92–2.75 (m, 2H), 2.74–2.62 (m, 1H), 2.37–2.27 (m, 3H), 1.74–1.64 (m, 2H), 1.64–1.50 (m, 3H), 1.49–1.43 (m, 3H), 1.32–1.22 (m, 5H), 1.21–1.15 (m, 3H).

[1107] Example 64: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-{3-[4-Fluoro-1-( 2 H 3 )Methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3-methylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-48)

[1108] The title compound was obtained by replacing B-1 with B-10 in a similar manner to Example 45.

[1109] ESI-MS (m / z): [M+H] + = 977.3.

[1110] 1 H NMR (400 MHz, DMSO d 6)δ8.36–8.23(m,3H),7.65(d,J=8.8Hz,1H),7.54–7.44(m,2H),7.40(d,J=6.8Hz,1H),7.36–7.25(m,2H),7.26–7.16(m,2H),7.10(d,J=3.1Hz,1H),7.00(s,1H),6.70–6.50(m,1H),5.73–5.63(m,1H),4.53–4.05(m,2H),3.75–3.58(m,5H),3.27–3.10(m,1H),3.08–2.99(m,1H),2.93–2.77(m,2H),2.75–2.63(m,1H),2.31–2.21(m,3H),1.74–1.65(m,2H),1.64–1.50(m,3H),1.49–1.43(m,3H),1.31–1.21(m,5H),1.21–1.15(m,3H).

[1111] Example 65: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyridin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-49)

[1112] The title compound was obtained by a method similar to Example 29, replacing 2-bromopyrimidine with 4-bromopyridine.

[1113] ESI-MS(m / z): [M+H] + = 987.3.

[1114] 1 H NMR(400MHz,DMSO-d 6)δ8.33(s,1H),8.23(s,2H),7.72 - 7.39(m,4H),7.34 - 7.07(m,5H),6.90(m,3H),5.69(m,1H),4.30(m,1H),4.12(s,3H),4.07(s,1H),3.91 - 3.61(m,4H),3.11 - 2.74(m,4H),2.26(s,6H),2.23 - 2.14(m,2H),1.75 - 1.40(m,7H),1.28(s,3H),1.23(s,2H),1.19(s,3H).

[1115] Example 66: 3 - [(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(5-fluoropyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-50)

[1116] The title compound was obtained by a method similar to Example 29 using 2-bromo-5-fluoropyridine in place of 2-bromopyrimidine.

[1117] ESI-MS(m / z): [M / 2 + H] + = 503.5.

[1118] 1 H NMR(400MHz, DMSO-d 6 )δ8.32(s,1H),8.05(m,1H),7.66(m,2H),7.56 - 7.42(m,3H),7.31(s,2H),7.19(m,2H),7.10(s,1H),6.94(m,1H),6.51(s,1H),5.71(s,1H),4.39 - 4.20(m,2H),4.17 - 4.02(m,5H),3.78 - 3.46(m,4H),3.09 - 2.98(m,2H),2.97 - 2.76(m,2H),2.30 - 2.16(m,7H),2.06 - 1.89(m,1H),1.74 - 1.35(m,5H),1.28(s,3H),1.23(s,2H),1.18(s,3H).

[1119] Example 67: 3-[(1R,5S,6S)-3-(5-chloropyridin-2-yl)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-51)

[1120] The title compound was obtained by substituting 2-bromo-5-chloropyridine for 2-bromopyrimidine according to a method similar to that of Example 29.

[1121] ESI-MS (m / z): [M+H] + = 1021.6.

[1122] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 8.04 (s, 1H), 7.87 - 7.41 (m, 5H), 7.30 (m, 2H), 7.20 (d, J = 6.4 Hz, 2H), 7.11 (d, J = 2.4 Hz, 1H), 7.03 - 6.36 (m, 2H), 5.70 (s, 1H), 4.45 - 4.22 (m, 2H), 4.17 - 4.02 (m, 5H), 3.78 - 3.51 (m, 4H), 3.24 - 2.97 (m, 2H), 2.95 - 2.62 (m, 2H), 2.26 (s, 6H), 2.23 - 2.10 (m, 1H), 2.06 - 1.89 (m, 1H), 1.76 - 1.37 (m, 5H), 1.28 (s, 3H), 1.23 (s, 2H), 1.19 (s, 3H).

[1123] Example 68: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-[5-(trifluoromethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-52)

[1124] The title compound was obtained by replacing 2-bromopyrimidine with 2-bromo-5-(trifluoromethyl)pyridine according to a method similar to that of Example 29.

[1125] ESI-MS (m / z): [M+H] + = 1055.6.

[1126] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.35 (m, J = 14.4 Hz, 2H), 7.81 - 7.62 (m, 3H), 7.50 (m, J = 7.2 Hz, 2H), 7.20 (m, 5H), 6.95 (m, 1H), 6.63 (m, 1H), 5.70 (m, 1H), 4.43 - 4.24 (m, 2H), 4.09 - 4.03 (m, 5H), 3.77 - 3.50 (m, 4H), 3.25 - 2.98 (m, 2H), 2.96 - 2.60 (m, 2H), 2.26 (s, 6H), 2.25 - 2.11 (m, 1H), 2.07 - 1.85 (m, 1H), 1.75 - 1.39 (m, 5H), 1.28 (s, 3H), 1.23 (s, 2H), 1.19 (s, 3H).

[1127] Example 69: 3-[(1R,5S,6S)-6-{2-[(4S)-2-(3-chloro-4-fluoro-5-methylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(4S)-2,2-dimethyloxacyclohexan-4-yl]-1H-indol-1-yl}-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-53)

[1128] The title compound was obtained by replacing B-1 with B-2 according to methods similar to those of Examples 29 and 38.

[1129] ESI-MS (m / z): [M+H] + = 998.5.

[1130] 1 H NMR (400 MHz, DMSO-d 6)δ8.34(s,1H),8.03(s,1H),7.67(d,J=8.8Hz,2H),7.49(d,J=8.8Hz,3H),7.36-7.27(m,3H),7.18(s,1H),7.10(s,1H),6.91(s,1H),6.60(s,1H),6.48(s,1H),5.73(s,1H),4.39-4.24(m,1H),4.12(s,3H),4.10-4.04(m,2H),3.72(d,J=8.4Hz,2H),3.60-3.48(m,2H),3.12-2.98(m,2H),2.95-2.80(m,2H),2.40-2.25(m,4H),2.03-1.96(m,2H),1.74-1.39(m,5H),1.28(s,3H),1.23(s,2H),1.19(s,3H).

[1131] Example 70: 3-[(1R,5S,6S)-6-{2-[(4S)-2-(3,4-difluoro-5-methylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indol-1-yl}-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-54)

[1132] The title compound was obtained by replacing B-1 with B-4 in a similar manner to Examples 29 and 38.

[1133] ESI-MS(m / z): [M+H] + = 992.3.

[1134] 1 H NMR(400MHz,DMSO-d 6)δ8.33(s,1H),8.03(s,1H),7.66(d,J=8.8Hz,1H),7.49(d,J=8.0Hz,3H),7.32(s,2H),7.24(s,1H),7.16(s,1H),7.07(s,1H),6.91(s,1H),6.64(d,1H),6.48(s,1H),5.72(s,1H),5.32(t,J=4.8Hz,1H),4.27(s,1H),4.16-4.04(m,5H),3.72(d,J=7.6Hz,2H),3.55(s,2H),3.12-2.97(m,2H),2.95-2.77(m,2H),2.38-2.26(m,4H),2.00(d,J=7.6Hz,2H),1.74-1.41(m,5H),1.28(s,3H),1.23(s,2H),1.19(s,3H).

[1135] Example 71: 5-[(4S)-5-{5-[(4S)-2,2-dimethyloxan-4-yl]-1-[(1R,5S,6S)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carbonyl}-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-2-yl]-2-fluoro-3-methylbenzonitrile (C-55)

[1136] The title compound was obtained by replacing B-1 with B-3 in a similar manner to Examples 29 and 38.

[1137] ESI-MS(m / z): [M+H] + = 998.5.

[1138] 1 H NMR(400MHz,DMSO-d 6)δ8.32(s,1H),8.03(s,1H),7.76(d,J=15.6Hz,2H),7.67(d,J=8.8Hz,1H),7.49(s,3H),7.31(s,1H),7.18(s,1H),7.09(s,1H),6.92(s,1H),6.64(d,J=26.0Hz,1H),6.48(s,1H),5.74(s,1H),5.33(d,J=4.8Hz,1H),4.40-4.21(m,1H),4.18-4.03(m,5H),3.78-3.65(m,2H),3.62-3.49(m,2H),3.13-2.96(m,2H),2,94-2,75(m,1H),2.41-2.26(m,4H),1.99(d,J=7.6Hz,2H),1.74-1.41(m,5H),1.28(s,3H),1.23(s,2H),1.19(s,3H).

[1139] Example 72: 3-[(1R,5S,6S)-6-{2-[(4S)-2-(3-chloro-4-fluoro-5-methylphenyl)-3-{3-[4-fluoro-1-( 2 H 3 )methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indol-1-yl}-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-56)

[1140] The title compound was obtained by replacing B-1 with B-6 in a similar manner to Examples 29 and 38.

[1141] ESI-MS (m / z): [M / 2 + H] + = 507.7.

[1142] 1 H NMR (400 MHz, DMSO-d 6)δ8.33(s,1H),8.07(s,1H),8.02(s,1H),7.67(d,J=8.8Hz,2H),7.54-7.36(m,6H),7.33(s,1H),7.16(s,1H),7.07(s,1H),6.69-6.44(m,1H),5.32(t,J=4.8Hz,1H),4.40-4.21(m,1H),4.03-3.99(m,2H),3.78-3.65(m,2H),3.62-3.49(m,2H),3.13-2.96(m,2H),2.94-2.75(m,1H),2.41-2.26(m,4H),1.99(d,J=7.6Hz,2H),1.74-1.41(m,5H),1.28(s,3H),1.23(s,2H),1.19(s,3H).

[1143] Example 73: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-{3-[4-Fluoro-1-( 2 H 3 )methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-[4-fluoro-3-methyl-5-(trifluoromethyl)phenyl]-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-57)

[1144] The title compound was obtained by replacing B-1 with B-9 in a similar manner to Examples 29 and 38.

[1145] ESI-MS (m / z): [M+H] + = 1044.6.

[1146] 11H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.03 (s, 1H), 7.84 - 7.62 (m, 3H), 7.60 - 7.37 (m, 4H), 7.36 - 7.15 (m, 3H), 7.14 - 6.85 (m, 1H), 6.69 - 6.44 (m, 2H), 5.74 (s, 1H), 4.50 - 3.84 (m, 3H), 3.72 (d, J = 8.0 Hz, 2H), 3.63 - 3.47 (m, 2H), 3.11 - 2.97 (m, 2H), 2.96 - 2.76 (m, 2H), 2.45 - 2.29 (m, 4H), 2.07 - 1.94 (m, 2H), 1.76 - 1.40 (m, 5H), 1.28 (s, 3H), 1.23 (s, 2H), 1.19 (s, 3H).

[1147] Example 74: 3-[(1R,5S,6S)-6-{2-[(4S)-2-(3-chloro-4-fluorophenyl)-3-{3-[4-fluoro-1-( 2 H 3 )methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyloxan-4-yl]-1H-indol-1-yl}-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-58)

[1148] The title compound was obtained by replacing B-1 with B-11 in a similar manner to Examples 29 and 38.

[1149] ESI-MS (m / z): [M+H] + = 996.4.

[1150] 11H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.98 (s, 2H), 7.84 - 7.35 (m, 7H), 7.34 - 7.04 (m, 2H), 6.76 - 6.44 (m, 2H), 6.31 (s, 1H), 5.71 (s, 1H), 5.35 - 5.29 (m, 1H), 4.27 - 3.81 (m, 3H), 3.78 - 3.66 (m, 2H), 3.64 - 3.47 (m, 2H), 3.11 - 2.92 (m, 2H), 2.89 - 2.56 (m, 2H), 2.06 - 1.92 (m, 3H), 1.75 - 1.38 (m, 5H), 1.28 (s, 3H), 1.23 (s, 2H), 1.19 (s, 3H).

[1151] Example 75: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-3-{3-[4-fluoro-1-( 2 H 3 )methyl-1H-indazol-5-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3-methylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl}-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-59)

[1152] The title compound was obtained by replacing B-1 with B-10 in a similar manner to Examples 29 and 38.

[1153] ESI-MS (m / z): [M + H] + = 976.5.

[1154] 1 1H NMR (400 MHz, DMSO-d 6)δ8.32(s,1H),8.16(s,1H),7.99(d,J=3.2Hz,2H),7.82-7.70(m,1H),7.65(d,J=8.8Hz,1H),7.56-7.16(m,4H),7.12-6.96(m,2H),6.76-6.44(m,2H),6.42-6.26(m,1H),5.74-5.65(m,1H),5.32(t,J=4.8Hz,1H),4.31-3.82(m,3H),3.72(d,J=8.0Hz,2H),3.64-3.48(m,2H),3.08-2.96(m,2H),2.76-2.64(m,2H),2.30-2.19(m,4H),2.04-1.94(m,2H),1.74-1.38(m,5H),1.28(s,3H),1.23(s,2H),1.19(s,3H).

[1155] Example 76: 3-[(1R,5S,6S)-6-{5-[(4S)-2,2-Dimethyloxan-4-yl]-2-[(4S)-3-[3-(4-Fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-5-carbonyl]-1H-indol-1-yl}-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (C-60)

[1156] The title compound was obtained by replacing B-1 with B-13 in a similar manner to Examples 18 and 29.

[1157] ESI-MS(m / z): [M+H] + = 973.7.

[1158] 1 H NMR(400MHz,DMSO-d 6)δ8.29(s,4H),7.72(d,J=7.6Hz,1H),7.64(s,1H),7.48(s,1H),7.28(d,J=22.4Hz,4H),7.05(s,1H),6.93(s,1H),6.80(s,1H),6.63(s,1H),4.94(s,2H),4.35(s,2H),4.11(s,4H),3.74-3.67(m,5H),3.07-2.95(m,2H),2.23(s,6H),2.06-1.94(m,1H),1.74-1.40(m,4H),1.28(s,3H),1.23(s,2H),1.19(s,3H).

[1159] Example 77: cAMP Accumulation Assay

[1160] Using the CHO-K1 cell line stably expressing human GLP-1R, the cAMP level was detected using the Hithunter cAMP Assay for small molecule platforms (DiscoverX, Cat#90-0075SM2) according to the manufacturer's instructions. The cells were seeded in a 96-well white plate (at a density of 2.5×10 4 per well) (Thermo, Cat#136101) and incubated in 1640 (Gibco, Cat#22400-071) supplemented with 10% FBS (fetal bovine serum, Hyclone Cat#SH30406.05), 800 μg / ml G418 (Gibco, Cat#10131-027) at 37 °C, 5% CO 2 . Briefly, the cells were treated with the compound or GLP-1 peptide (10 points, 3-fold dilution) in PBS (phosphate buffered saline, Gibco, Cat#10010-023) containing 1% BSA (bovine serum albumin, Sigma Cat#V900933-100G). After incubation at 37 °C for 30 minutes, the cAMP antibody reagent, working solution (mix 19 parts lysis buffer, 5 parts substrate reagent 1, 1 part substrate reagent 2, and 25 parts solution D (enzyme donor-labeled cAMP)) and solution A (enzyme acceptor) were added and incubated at room temperature in the dark. The resulting competitive assay was measured using a Spectramax i3x multimode detection system (Molecular Devices, USA). The relative EC 50 obtained by non-linear regression analysis was fitted to a 4-parameter logistic model in GraphPad Prism 9 software.

[1161] The data for the compounds and peptides are shown in Table 2 below.

[1162] Table 2: Functional cAMP potency (EC 50 ) of the compounds and controls in the presence of BSA

[1163]

[1164]

[1165]

[1166] Example 78: Pharmacokinetic testing in cynomolgus monkeys

[1167] The compounds of the present invention were administered to cynomolgus monkeys by intravenous injection and oral gavage, respectively. Plasma samples were collected at different time points. The drug concentration of the test compounds in the plasma tissues of cynomolgus monkeys was detected by LC-MS / MS analysis method, and pharmacokinetic analysis was carried out.

[1168] 1. Preparation of dosing formulations

[1169] Solvent for intravenous injection dosing formulation: 5% dimethyl sulfoxide (DMSO) + 5% polyethylene glycol (PEG)-15 hydroxystearic acid + 90% normal saline.

[1170] Preparation steps of the solution for intravenous injection: Accurately weigh the compound and add it to the above solvent for intravenous injection to prepare a solution with a final concentration of 0.25 mg / mL.

[1171] Solvent for oral dosing formulation: 5% dimethyl sulfoxide (DMSO) + 5% polyethylene glycol (PEG)-15 hydroxystearic acid + 90% normal saline.

[1172] Preparation steps of the solution for oral administration: Accurately weigh the compound and add it to the above solvent for oral administration to prepare a solution or suspension with a final concentration of 0.4 mg / mL.

[1173] 2. Administration

[1174] Intravenous injection (IV): Administered by injection through the tail vein. After inserting the needle, slowly pull back the syringe to check for blood return, indicating that the needle is in the vein, and then inject the drug solution.

[1175] Oral (PO): Select a gavage needle and syringe of appropriate size, insert the gavage needle from the root of the tongue into the esophagus until it is close to the cardia of the stomach, then inject the drug solution and remove the gavage needle. When using a disposable plastic feeding needle, one needle is used for each group.

[1176] 3. Blood sample collection and processing

[1177] Blood was collected via the cephalic vein or other suitable veins, approximately 1 mL for each sample, anticoagulated with K2-EDTA, and placed on ice after collection. After collection, the blood samples were stored on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 2200 g, 10 minutes, 2 - 8 °C). The plasma samples were stored at -80 °C before analysis, and the remaining plasma samples after analysis were continued to be stored at -80 °C.

[1178] 4. Sample detection Plasma concentration detection: In this experiment, a mature LC-MS / MS method was used to detect the compounds in plasma.

[1179] 5. Data analysis: Using (Version 7.0, Pharsight, MountainView, CA), non-compartmental model was used to analyze the blood concentration-time data.

[1180] Table 4:

[1181]

[1182] According to the test data, compounds C-12 and C-22 showed longer half-lives, higher exposures, lower clearance rates, and better bioavailability in cynomolgus monkeys than orforglipron. This indicates that the compounds of this patent show better absorption characteristics in cynomolgus monkeys. Other benefits of these compounds may include improved solubility, weight loss, and / or blood glucose reduction.

[1183] Orforglipron:

[1184]

[1185] Although the present invention has disclosed specific embodiments, those skilled in the art can understand that certain substitutions, changes, and / or omissions can be made to the embodiments without departing from the spirit of the present invention. Therefore, the above description (the above specification) is only for example and should not limit the scope of the present invention. All references cited herein (including those listed above), scientific articles, patent publications, and any other documents are incorporated herein by reference to the substance of their disclosures.

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein: R 1 , R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 Alkoxy); L 1 and L 2 each independently is a linker; X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom, and optionally where a double bond exists between Q and an adjacent carbon atom and / or between Y and Z); A is optionally substituted aryl (such as optionally substituted C 6-10 Aryl, for example optionally substituted phenyl) (such as, wherein the optional substituents include halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); B is an optionally substituted heterocyclyl (such as an optionally substituted 5-10 membered heterocyclyl, for example an optionally substituted bicyclic 5-10 membered heterocyclyl; an optionally substituted 5-10 membered heteroaryl, for example an optionally substituted indole) (such as, wherein B may be optionally replaced by V 1 Replace, where V 1 is optionally substituted heterocyclyl (such as optionally substituted 5-10 membered heterocyclyl); C is in U 1 is oxy (such as, -O-), thio (such as, -S-), sulfinyl (such as, -S(O)-), sulfonyl (such as, -S(O)2-), optionally substituted amino (such as, -N(R ua )-) or optionally substituted alkylene (such as, optionally substituted C 1-6 Alkylene); U 2 is O, -N(R ua )-or S; n1 and n2 are each independently 0, 1, 2, or 3 (such as, wherein at least one of n1 and n2 is not 0); R ua are each independently hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted heterocyclyl (such as, optionally substituted 5-10 membered heterocyclyl) (such as, wherein the optional substituents include C 1-6 Alkyl, halogen, C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted sulfonyl (such as, -S(O)2-) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl); and R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or isotopes, wherein there may be one or more R uc exist on the rings to which they are attached, and D is an optionally substituted heterocyclyl (such as an optionally substituted 5-10 membered heterocyclyl, for example an optionally substituted bicyclic 5-10 membered heterocyclyl) (such as wherein the optional substituents include halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 1 , R 2 and R 3 Each is independently hydrogen (H) or optionally substituted alkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein X and Y are each N, Y and Z are each N, or Y and Q are each N.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein X is N, and wherein the first double bond exists between Q and the adjacent carbon atom and the second double bond exists between Y and Z.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein Z is N, and wherein the first double bond exists between Q and the adjacent carbon atom and the second double bond exists between X and Y.

6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein Q is N, and wherein the first double bond exists between X and the adjacent carbon atom and the second double bond exists between Y and Z.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein L 1 is a carbonyl group (such as, -C(O)-), an alkylene group (such as, optionally substituted C 1-6 alkylene), sulfinyl (such as, -S(O)-) or sulfonyl (such as, -S(O)2-).

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein L 2 yes And among them: n4 is 1, 2, or 3, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom); and R La and R Lb (if present) are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), and optionally wherein R La and R Lb Together with the nitrogen atom to which they are attached they form an optionally substituted heterocyclyl.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein A is an optionally substituted C 6-10 Aryl, and wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, or C 3-8 Halogenated cycloalkyl.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein A is Where R 5 , R 6 and R 7 are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) or optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein A is 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein B is and in: W 1 , W 3 and W 4 each independently is C or N; W 2 Yes CR wa NR wa , N, O, or S, and dashed lines represent optional double bonds (such as, where two double bonds are not attached to the same atom); W 5 , W 6 and W 7 Each is independently CR wa or N (such as, wherein b1, b2 and b3 are connected to L in any order or position 1 , C and V 1 );and R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein B is 14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein B is 15. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein B is and in: W 1 , W 3 and W 4 each independently is C or N; W 2 Yes CR wa NR wa , N, O, or S, and dashed lines represent optional double bonds (such as, where two double bonds are not attached to the same atom); W 5 , W 6 and W 7 Each is independently CR wa or N (such as, where b1 and b2 are connected to L in any order or position 1 and C); and R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein B is 17. The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein V 1 yes and in: V a Is N or CR vc ; V b YesNR Vc , O, or S; R va and R vc (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination thereof), and one or more R va Exists in V 1 superior.

18. The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein V 1 yes And among them: V a Is N or CR vc , R va , R vb and R vc (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein C is or a stereoisomer thereof.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein C is or a stereoisomer thereof.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein C is or a stereoisomer thereof, optionally wherein U 2 It's O.

22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein C is or a stereoisomer thereof.

23. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein C is or a stereoisomer thereof.

24. The compound of any one of claims 1-18 or 23, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein C is or a stereoisomer thereof.

25. The compound of any one of claims 1-18, 23 or 24, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein C is or a stereoisomer thereof.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein U 1 is optionally substituted C 1-6 Alkylene (such as -CR ua R ub -or-[CR Ua R Ub ] n3 -, wherein n3 is 1, 2, or 3, and wherein R ua and R ub (if present) are each independently hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 Alkoxy)).

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein U 1 Yes-N(R ua )-.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R ua are independently hydrogen (H), C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heterocyclic group, -S(O)2- or C 3-8 Cycloalkyl, where R ua C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heterocyclic group, -S(O)2- or C 3-8 The cycloalkyl groups are each independently optionally substituted by halogen, oxo, hydroxy, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 3-8 Cycloalkyl.

29. The compound of claim 27 or 28, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R ua is an unsubstituted 5-10 membered heteroaryl group.

30. The compound of claim 27 or 28, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R ua It is a 6-membered heterocyclic group.

31. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein C is 32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein D is And among them: R da , R bd , R dc and R dd are each independently hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy); and R 4 is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 Cycloalkyl) (such as, wherein the optional substituents include halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein D is 34. The compound of claim 32, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein D is 35. The compound of claim 1, wherein the compound is of formula (IIa): or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein: R 1 , R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 Alkoxy); R 4 is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 Cycloalkyl); R 5 , R 6 and R 7 are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) or optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); L 1 and L 2 each independently is a linker; X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom, and optionally where a double bond exists between Q and an adjacent carbon atom and / or between Y and Z); W 1 , W 3 and W 4 each independently is C or N; W 2 Yes CR wa NR wa , N, O, or S, and dashed lines represent optional double bonds (such as, where two double bonds are not attached to the same atom); W 5 , W 6 and W 7 Each is independently CR wa or N; R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); U 1 is oxy (such as, -O-), thio (such as, -S-), sulfinyl (such as, -S(O)-), sulfonyl (such as, -S(O)2-), optionally substituted amino (such as, -N(R ua )-) or optionally substituted alkylene (such as, optionally substituted C 1-6 Alkylene); U 2 is O or S; R ua are each independently hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 Cycloalkyl); R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or isotopes, wherein one or more R uc exist on the rings to which they are attached; and n1 and n2 are each independently 0, 1, 2, or 3 (such as, wherein at least one of n1 and n2 is not 0).

36. The compound of claim 1, wherein the compound is of formula (IIb): or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein: R 1 , R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 Alkoxy); R 4 is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 Cycloalkyl); R 5 , R 6 and R 7 are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) or optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); R La and R Lb (if present) are each independently hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), and optionally wherein R La and R Lb each together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl; X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom, and optionally where a double bond exists between Q and an adjacent carbon atom and / or between Y and Z); W 1 , W 3 and W 4 each independently is C or N; W 2 Yes CR wa NR wa , N, O, or S, and dashed lines represent optional double bonds (such as, where two double bonds are not attached to the same atom); W 5 , W 6 and W 7 Each is independently CR wa or N; R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); U 1 is oxy (such as, -O-), thio (such as, -S-), sulfinyl (such as, -S(O)-), sulfonyl (such as, -S(O)2-), optionally substituted amino (such as, -N(R ua )-) or optionally substituted alkylene (such as, optionally substituted C 1-6 Alkylene); U 2 is O or S; R ua are each independently hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 Cycloalkyl); R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or isotopes, wherein there may be one or more R uc are present on the ring to which they are attached, and n1 and n2 are each independently 0, 1, 2, or 3 (such as, wherein at least one of n1 and n2 is not 0).

37. The compound of claim 1, wherein the compound is of the structure of formula (IIc): or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein: R 1 , R 2 and R 3 are each independently hydrogen (H), halogen, hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 Alkoxy); R 4 is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 Cycloalkyl); R 5 , R 6 and R 7 are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) or optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom, and optionally where a double bond exists between Q and an adjacent carbon atom and / or between Y and Z); W 1 , W 3 and W 4 each independently is C or N; W 2 Yes CR wa NR wa , N, O, or S, and dashed lines represent optional double bonds (such as, where two double bonds are not attached to the same atom); W 5 , W 6 and W 7 Each is independently CR wa or N; R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); U 1 is oxy (such as, -O-), thio (such as, -S-), sulfinyl (such as, -S(O)-), sulfonyl (such as, -S(O)2-), optionally substituted amino (such as, -N(R ua )-) or optionally substituted alkylene (such as, optionally substituted C 1-6 Alkylene); U 2 is O or S; R ua are each independently hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) or optionally substituted alkoxy (such as, optionally substituted C 1-6 Alkoxy); R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or isotopes, wherein one or more R uc present on the ring to which they are attached; and n1 and n2 are each independently 0, 1, 2, or 3 (such as, wherein at least one of n1 and n2 is not 0).

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof), or a solvate thereof, wherein X is N; X and Y are N; Y and Z are N; or Y and W are N.

39. The compound of any one of claims 35-38, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , or W 7 At least one of them is independently N or NR wa ; and where R wa is hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof), or a solvate thereof, wherein R 1 is optionally substituted alkyl (such as optionally substituted C 1-6 alkyl).

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 1 , R 2 and R 3 At least one of them is not H.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof), or a solvate thereof, wherein R 4 It is C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, 3-8 Cycloalkyl substituted C 1-6 Alkyl, or one or more C 3-8 Halogenated cycloalkyl substituted C 1-6 alkyl.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 5 , R 6 and R 7 are independently halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, 3-8 Cycloalkyl substituted C 1-6 Alkyl, or one or more C 3-8 Halogenated cycloalkyl substituted C 1-6 alkyl.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 6 is a halogen (such as fluorine or chlorine).

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 5 and R 7 are each independently halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

46. ​​The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 5 , R 6 and R 7 At least one of them is not H.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein U 1 It is O or methylene (CH2).

48. The compound of any one of claims 47, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof), or a solvate thereof, wherein U 1 It's O.

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein n1 is 1 and / or wherein n2 is 1.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein U 2 is O and / or R ua Is H or C 1-6 alkyl.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein U 2 It's O.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein V 1 yes And among them: V a Is N or CR vc , R va , R vb and R vc (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

53. The compound of claim 1, wherein the compound is of the structure of formula (IIIa): or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein: U 1 is oxy (such as, -O-), thio (such as, -S-), sulfinyl (such as, -S(O)-), sulfonyl (such as, -S(O)2-), optionally substituted amino (such as, -N(R ua )-) or optionally substituted alkylene (such as, optionally substituted C 1-6 Alkylene); R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or isotopes, wherein one or more R uc present on the ring to which they are attached; and n1 is 0, 1, 2, or 3.

54. The compound of claim 53, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein V 1 yes and in: V a Is N or CR vc , R va and R vc (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, or any combination of these), and wherein one or more R va Can exist in V 1 superior.

55. The compound of claim 53, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein V 1 yes And among them: V a Is N or CR vc , R va , R vb , and R vc (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these).

56. The compound of claim 1, wherein the compound is of the structure of formula (IIIb): or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein: R 4 is hydrogen (H), optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy) or optionally substituted cycloalkyl (such as, optionally substituted C 3-8 Cycloalkyl); R 5 , R 6 and R 7 are each independently hydrogen (H), halogen, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl) or optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); and R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or isotopes, wherein there may be one or more R uc Exist on the rings to which they are connected.

57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 4 It is C 1-6 Alkyl (such as methyl), deuterated C 1-6 Alkyl (such as deuterated methyl, for example CD3), C 3-8 Cycloalkyl (such as cyclopropyl, for example ), by one or more C 3-8 Cycloalkyl substituted C 1-6 Alkyl (such as, cyclopropylalkyl, including cyclopropylmethyl, such as ), C 3-8 Halogenated cycloalkyl (such as, 1-halogenated cyclopropyl, including 1-fluorocyclopropyl, such as ) or by one or more C 3-8 Halogenated cycloalkyl substituted C 1-6 Alkyl (such as, 1-halocyclopropylalkyl, including 1-fluorocyclopropylmethyl, such as ).

58. The compound of claim 56 or 57, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 5 , R 6 and R 7 are each independently halogen (such as fluorine or chlorine), C 1-6 Alkyl (such as methyl), C 3-8 Cycloalkyl (such as cyclopropyl, for example C 3-8 Cycloalkyl (such as cyclopropyl), 3-8 Cycloalkyl substituted C 1-6 Alkyl (such as cyclopropylalkyl, including cyclopropylmethyl), C 3-8 Halogenated cycloalkyl (such as 1-halogenated cyclopropyl, including 1-fluorocyclopropyl) or substituted by one or more C 3-8 Halogenated cycloalkyl substituted C 1-6 Alkyl (such as 1-halocyclopropylalkyl, including 1-fluorocyclopropylmethyl).

59. The compound of claim 1, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein the compound is of formula (IIIc): or a pharmaceutically acceptable salt, a stereoisomer, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein: Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond (such as where two double bonds are not attached to the same atom, and optionally where a double bond exists between Q and an adjacent carbon atom and / or between Y and Z); W 1 , W 3 and W 4 each independently is C or N; W 2 Yes CR wa NR wa , N, O, or S, and dashed lines represent optional double bonds (such as, where two double bonds are not attached to the same atom); W 5 , W 6 and W 7 Each is independently CR wa or N; R wa (if present) are each independently hydrogen (H), halogen, or optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl) (such as, wherein the optional substituents include one or more of the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 halocycloalkyl, or any combination of these); and R uc are each independently hydrogen (H), hydroxy, optionally substituted alkyl (such as, optionally substituted C 1-6 alkyl), optionally substituted haloalkyl (such as, optionally substituted C 1-6 haloalkyl), optionally substituted alkoxy (such as, optionally substituted C 1-6 alkoxy), optionally substituted haloalkoxy (such as, optionally substituted C 1-6 haloalkoxy), optionally substituted cycloalkyl (such as, optionally substituted C 3-8 cycloalkyl), optionally substituted halocycloalkyl (such as, optionally substituted C 3-8 halocycloalkyl), amino (such as, -NR N1 R N2 , as described herein) or isotopes, wherein there may be one or more R uc Exist on the rings to which they are connected.

60. The compound of claim 59, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein yes 61. The compound of claim 59 or 60, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein yes 62. The compound of claim 1, wherein the compound is of formula (IV): or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein: R 1 , R 2 and R 3 are independently hydrogen (H), halogen, hydroxyl, C 1-6 Alkyl, or C 1-6 Alkoxy; R 4 It is hydrogen (H), halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, or C 3-8 Halogenated cycloalkyl; R 5 , R 6 and R 7 are independently hydrogen (H), halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, or C 3-8 Halogenated cycloalkyl; X, Y, Z, and Q are each independently C or N, and the dashed line represents an optional double bond; W 1 , W 3 and W 4 each independently is C or N; W 2 Yes CR wa NR wa , N, O, or S, and the dashed line represents an optional double bond; W 5 , W 6 and W 7 Each is independently CR wa or N; R wa (if present) are each independently hydrogen (H), halogen, or C 1-6 alkyl; C is Optionally wherein C is U 1 It is -O-, -S-, -S(O)-, -S(O)2-, -N(R ua )- or -CH2-; U 2 is O, -N(R ua )- or S; optionally, U 2 is O or S; R ua are independently hydrogen (H), C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heterocyclic group, -S(O)2- or C 3-8 Cycloalkyl, wherein R ua C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heterocyclic group, -S(O)2- or C 3-8 The cycloalkyl groups are each independently optionally substituted by halogen, oxo, hydroxy, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 3-8 Cycloalkyl; R uc are independently hydrogen (H), hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, -NR N1 R N2 or isotopes, which may contain one or more R uc Exist on the ring to which they are connected; where R N1 and R N2 Each independently is H, C 1-6 Aliphatic, C 1-6 Alkyl, C 1-6 Heteroaliphatic, C 1-6 heteroalkyl, aromatic, or aryl; or wherein R N1 and R N2 Together with the nitrogen atom to which they are each attached, they form a heterocyclic group; n1 and n2 are each independently 0, 1, 2, or 3; and V 1 yes in: V a Is N or CR vc ,and R va , R vb , and R vc (if present) are each independently hydrogen (H), halogen, or C 1-6 alkyl.

63. The compound of claim 62, wherein the compound of formula (IV) is a compound of formula (IVa) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof.

64. The compound of claim 62, wherein the compound of formula (IV) is a compound of formula (IVb) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof.

65. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein C is Optionally wherein C is 66. The compound of any one of claims 62-65, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 4 It is -CH3.

67. The compound of any one of claims 62-66, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 5 and R 7 Each is -CH3.

68. The compound of any one of claims 62-67, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 6 It's a halogen.

69. The compound of any one of claims 62-68, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein U 1 Yes-N(R ua )-.

70. The compound of claim 69, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R ua It is a 5-10 membered heterocyclic group.

71. The compound of claim 69 or 70, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R ua It is a 6-membered heterocyclic group.

72. The compound of any one of claims 62-71, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein V 1 yes 73. The compound of any one of claims 62-72, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein U 2 It's O.

74. The compound of claim 62, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein B is 75. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein R 1 and R 2 is independently H, optionally substituted alkyl, or optionally substituted alkoxy; optionally, wherein R 1 and R 2 is independently hydrogen (H) or optionally substituted alkyl.

76. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, wherein U 2 It is O or S.

77. A compound according to Table 1, or a pharmaceutically acceptable salt, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof.

78. A compound according to Table 3c, or a pharmaceutically acceptable salt, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof.

79. A pharmaceutical composition comprising a compound of any one of claims 1-78, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, and at least one pharmaceutically acceptable excipient.

80. A method for treating or prophylactically treating a GLP-1-related disease, disorder or condition, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of claims 1-78, or a pharmaceutically acceptable salt, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, or a pharmaceutical composition of claim 79.

81. The method of claim 80, wherein the disease, disorder or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early onset type 2 diabetes, idiopathic type 1 diabetes, 1b), youth-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), overweight, weight gain caused by use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, hyperlipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, atherosclerosis, coronary heart disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, cerebral infarction, peripheral vascular disease, endothelial dysfunction, vascular compliance impairment, vascular restenosis, thrombosis, hypertension, pulmonary artery Hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depression, skin and connective tissue disease, foot ulcer, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, dementia, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

82. A method for treating or prophylactically treating diabetes in an individual in need thereof, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of claims 1-78, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, or a pharmaceutical composition of claim 79.

83. A method for treating or prophylactically treating type 2 diabetes in an individual in need thereof, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of claims 1-78, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, or a pharmaceutical composition of claim 79.

84. A method for treating or prophylactically treating obesity or overweight in an individual in need thereof, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of claims 1-78, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, or a pharmaceutical composition of claim 79.

85. A method of regulating insulin levels in an individual in need of such regulation, the method comprising administering to the individual in need thereof an effective amount of a compound of any one of claims 1-78, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof) or a solvate thereof, or a pharmaceutical composition of claim 79.

86. A method of regulating glucose levels in an individual in need of such regulation, the method comprising administering to the individual in need thereof an effective amount of a compound of any one of claims 1-78, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an analog thereof (such as a deuterated analog thereof), or a solvate thereof, or a pharmaceutical composition of claim 79.

87. The method of any one of claims 80-86, further comprising administering to the individual an additional therapy or therapeutic agent.

88. The method of claim 87, wherein the additional therapy or therapeutic agent is selected from the group consisting of an antidiabetic agent, an antiobesity agent, a GLP-1 receptor agonist, an antiemetic, an agent for treating nonalcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

89. A compound according to any one of claims 1 to 78, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analog thereof (such as a deuterated analog thereof), or a solvate thereof, for use in the treatment or prophylactic treatment of a GLP-1 related disease, disorder or condition.

90. Use of a compound of any one of claims 1-78, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an analog thereof (such as a deuterated analog thereof), or a solvate thereof, in the preparation of a medicament for the treatment or prophylactic treatment of a GLP-1-related disease, disorder, or condition.

91. The compound for use of claim 89 or the use of claim 90, wherein the disease, disorder or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (Type 1b), youth-onset atypical diabetes (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), overweight, weight gain caused by the use of other medications, idiopathic Intracranial hypertension, Wolfram syndrome, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, hyperlipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, atherosclerosis, coronary heart disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, cerebral infarction , peripheral vascular disease, endothelial dysfunction, vascular compliance impairment, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depression, skin and connective tissue diseases, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, dementia, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

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